Cbl

UniProt ID: P22682
Organism: Mus musculus
Review Status: COMPLETE
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Gene Description

Cbl is a RING-type E3 ubiquitin-protein ligase and phosphotyrosine-binding adaptor that recognizes activated receptor tyrosine kinases and other signaling proteins. It ubiquitinates receptors and signaling components to promote endocytosis, lysosomal or proteasomal turnover, and negative feedback on EGFR, PDGFRA, KIT, CSF1R, SRC-family, and immune-receptor signaling pathways.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0061630 ubiquitin protein ligase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
Reason: Site where Cbl engages activated membrane receptors; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0007165 signal transduction
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Very broad BP (IBA) consistent with Cbl as a signaling protein; correct but unspecific, retained as non-core context.
Reason: High-level signaling context; correct but non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).
GO:0045121 membrane raft
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Cbl colocalizes with FGFR2 in lipid rafts at the cell membrane (UniProt Note); a microdomain refinement of its membrane recruitment (IBA).
Reason: Lipid-raft microdomain localization; refinement of membrane recruitment, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0030971 receptor tyrosine kinase binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Cbl binds activated RTKs (KIT, FLT1, PDGFRA/B, CSF1R, EPHA8, KDR, EGFR) via its TKB domain as the substrate-selection step of receptor downregulation (IBA).
Reason: Core recognition of RTK substrates; central to Cbl's negative-regulator role.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.
GO:0001784 phosphotyrosine residue binding
IEA
GO_REF:0000002 		ACCEPT
Summary: Core substrate-recognition MF: the TKB/PTB (SH2-like) domain binds phosphotyrosine on activated receptors, the mechanism by which Cbl selects substrates.
Reason: Defines how Cbl recognizes activated, phosphorylated receptor substrates; core adaptor MF.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.
GO:0004842 ubiquitin-protein transferase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Core catalytic MF (EC 2.3.2.27) describing the ubiquitin transfer reaction Cbl catalyzes; equivalent framing of its RING E3 activity, retained as a core function.
Reason: Core catalytic activity matching the UniProt CATALYTIC ACTIVITY/EC 2.3.2.27 reaction.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0005509 calcium ion binding
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Cbl has one functional Ca2+-binding EF-hand within the TKB domain (structural/regulatory), but Ca2+ binding is not a core function and is captured by the TKB domain architecture.
Reason: Single structural EF-hand Ca2+ site; not a core MF.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Consistent with UniProt SUBCELLULAR LOCATION (Cytoplasm); a correct, if general, parent localization for the cytosolic Cbl pool.
Reason: Matches UniProt cytoplasmic localization; general but correct core compartment.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005794 Golgi apparatus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
Reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0005886 plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
Reason: Site where Cbl engages activated membrane receptors; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005929 cilium
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
Reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0007166 cell surface receptor signaling pathway
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Broad pathway term (IEA) situating Cbl within receptor signaling; correct but unspecific, retained as non-core context.
Reason: Broad correct context term; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).
GO:0008270 zinc ion binding
IEA
GO_REF:0000043 		MARK AS OVER ANNOTATED
Summary: Reflects the structural Zn(2+) coordinated by the RING-type zinc finger; structural, not an independent function, and subsumed by the E3 ligase activity annotation.
Reason: Structural zinc of the RING domain; over-annotated as a standalone MF.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.
GO:0016740 transferase activity
IEA
GO_REF:0000043 		MODIFY
Summary: Bare 'transferase activity' is far too generic for an E3 ligase whose specific activity is ubiquitin transfer; replace with the specific ubiquitin-protein transferase term.
Reason: Uninformatively general parent of the specific ubiquitin transferase activity.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0023051 regulation of signaling
IEA
GO_REF:0000002 		MODIFY
Summary: Top-level vague term; Cbl predominantly negatively regulates signaling by receptor downregulation, so refine to negative regulation of signal transduction.
Reason: Very general; replace with the negative-regulation child reflecting Cbl's role.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).
GO:0046872 metal ion binding
IEA
GO_REF:0000120 		MARK AS OVER ANNOTATED
Summary: Generic parent of the structural zinc/calcium binding; uninformative and not a function in its own right.
Reason: Generic metal-binding term with no independent functional meaning.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.
GO:0061630 ubiquitin protein ligase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:1902531 regulation of intracellular signal transduction
IEA
GO_REF:0000117 		MODIFY
Summary: Overly broad; Cbl's documented role is negative regulation via receptor ubiquitination/downregulation, better captured by negative regulation of signal transduction.
Reason: Too general; a more specific negative-regulation child is available.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).
GO:2000583 regulation of platelet-derived growth factor receptor-alpha signaling pathway
IEA
GO_REF:0000117 		ACCEPT
Summary: Cbl (with Cbl-b) provides feedback inhibition of ciliary PDGFRA signaling via PDGFRA ubiquitination and internalization (IMP:UniProtKB; PubMed:29237719).
Reason: Specific, experimentally supported PDGFRA negative-feedback role; mirrors UniProt FUNCTION.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-family ubiquitination of activated RTKs (EGFR paradigm) is a central, experimentally grounded function that links phosphorylation-dependent recognition to endosomal sorting and receptor downregulation.
GO:0005515 protein binding
IPI
PMID:12559036
CD2AP/CMS regulates endosome morphology and traffic to the d... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:23374343
Induction of Siglec-G by RNA viruses inhibits the innate imm... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:23799367
Threshold-controlled ubiquitination of the EGFR directs rece... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:24440350
Targeting of the MET receptor tyrosine kinase by small molec... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:27474268
Co-recruitment analysis of the CBL and CBLB signalosomes in ... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:7657591
Tyrosine phosphorylation of the c-cbl proto-oncogene protein... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:9890970
Fyn associates with Cbl and phosphorylates tyrosine 731 in C... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0000209 protein polyubiquitination
IEA
GO_REF:0000107 		ACCEPT
Summary: Cbl multi/poly-ubiquitinates activated RTKs (e.g. CSF1R multiubiquitination), a documented degradative outcome of its ligase activity.
Reason: Specific, correct ubiquitin-chain type produced by Cbl on receptor substrates.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0005829 cytosol
IEA
GO_REF:0000120 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005925 focal adhesion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Focal-adhesion localization (IEA/ISO) fits Cbl's roles in adhesion/cytoskeletal signaling; a context-specific site rather than a core compartment.
Reason: Context-specific adhesion-site localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0006511 ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).
Reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0006513 protein monoubiquitination
IEA
GO_REF:0000107 		ACCEPT
Summary: Cbl also monoubiquitinates receptors, a recognized signal for endocytic sorting; a valid specific ubiquitination outcome of Cbl.
Reason: Documented mono-ubiquitination activity supporting receptor internalization.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0006974 DNA damage response
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Single IEA annotation with no established Cbl-specific mechanism; weak but not contradicted, so retained as non-core rather than removed.
Reason: Weak electronic annotation; retain as non-core, mechanism unclear.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.
GO:0008584 male gonad development
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Developmental annotation (IEA) reflecting pleiotropic roles in organ development; not a core molecular mechanism.
Reason: Pleiotropic developmental role; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In intestine, c-Cbl and Cbl-b are partly redundant
GO:0010332 response to gamma radiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA stimulus-response term tied to DNA-damage context; peripheral and without specific Cbl mechanism.
Reason: Generic radiation-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0014823 response to activity
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Broad stimulus-response term (IEA) lacking a specific Cbl mechanism; peripheral contextual annotation.
Reason: Vague stimulus-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0016567 protein ubiquitination
IEA
GO_REF:0000120 		ACCEPT
Summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
Reason: Direct experimental annotation of Cbl's core ubiquitination process.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0017124 SH3 domain binding
IEA
GO_REF:0000120 		MARK AS OVER ANNOTATED
Summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
Reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0019901 protein kinase binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Redundant generic kinase-binding term superseded by the more specific protein/receptor tyrosine kinase binding annotations that describe Cbl's actual substrate recognition.
Reason: Generic and redundant with the specific tyrosine-kinase-binding MFs.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0030424 axon
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Axonal localization (IEA/ISO) is a neuronal-context site consistent with Eph-receptor regulation; not a core compartment for the E3/adaptor function.
Reason: Neuronal-context localization; specialized, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0030426 growth cone
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Growth-cone localization (IEA/ISO) reflects neuronal/cytoskeletal context (e.g. Eph signaling); peripheral specialized localization.
Reason: Neuronal context localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0033574 response to testosterone
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA hormone-response term, likely tied to gonad context; peripheral with no specific Cbl mechanism.
Reason: Generic hormone-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0036120 cellular response to platelet-derived growth factor stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cbl acts in PDGF receptor signaling responses (IEA); the mechanistic core (PDGFRA regulation) is captured separately, so this broad response is non-core.
Reason: Broad PDGF-response context; mechanism captured by the PDGFRA-regulation term.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0036312 phosphatidylinositol 3-kinase regulatory subunit binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Phospho-Cbl interacts with PIK3R1 to recruit PI3K (UniProt SUBUNIT); a genuine partner interaction supporting PI3K coupling but downstream of Cbl's core E3 role.
Reason: Documented PIK3R1 interaction; secondary/effector partner binding, not core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IEA
GO_REF:0000120 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0042594 response to starvation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA nutrient-deprivation response with no Cbl-specific mechanism; peripheral contextual annotation.
Reason: Generic starvation-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0043066 negative regulation of apoptotic process
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
Reason: Pleiotropic survival-signaling outcome; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.
GO:0043303 mast cell degranulation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cbl modulates mast-cell signaling (KIT/FcεRI) affecting degranulation (IEA); a downstream cell-type-specific physiological readout.
Reason: Cell-type-specific physiological outcome; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0045471 response to ethanol
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Single IEA stimulus-response annotation with no Cbl-specific mechanism; peripheral.
Reason: Generic chemical-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:0046875 ephrin receptor binding
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
Reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Receptor tyrosine kinases (RTKs)
GO:0048260 positive regulation of receptor-mediated endocytosis
IEA
GO_REF:0000107 		ACCEPT
Summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
Reason: Cbl actively drives receptor internalization — core downregulation mechanism.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0048471 perinuclear region of cytoplasm
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Perinuclear localization (IEA/ISO) is consistent with endosomal/recycling trafficking compartments; a sub-cytoplasmic refinement, non-core.
Reason: Sub-cytoplasmic trafficking-compartment localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0050821 protein stabilization
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
Reason: Runs counter to Cbl's degradative role; likely over-annotation.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0050860 negative regulation of T cell receptor signaling pathway
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
Reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0050868 negative regulation of T cell activation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
Reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0051865 protein autoubiquitination
IEA
GO_REF:0000107 		ACCEPT
Summary: Cbl undergoes autoubiquitination (it is itself ubiquitinated leading to proteasomal turnover, per UniProt PTM), a genuine regulatory activity of the RING ligase.
Reason: Self-ubiquitination is a documented PTM/activity consistent with RING E3 function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Phospho-Cbl recruits PI3K (e.g. Tyr-731 form in osteoclasts) promoting PI3K/AKT signaling; a context-specific positive role distinct from its main negative-regulator function.
Reason: Context-specific PI3K/AKT-promoting role; downstream, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
GO:0070534 protein K63-linked ubiquitination
IEA
GO_REF:0000107 		MODIFY
Summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
Reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
Proposed replacements: protein ubiquitination
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0071456 cellular response to hypoxia
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Hypoxia-response annotation (IEA) is a contextual stimulus-response with no specific Cbl mechanism asserted; peripheral.
Reason: Generic stimulus-response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:1990090 cellular response to nerve growth factor stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Reflects Cbl participation downstream of NGF/TrkA receptor signaling (IEA); a context response rather than a core mechanism.
Reason: Downstream growth-factor response context; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
GO:1990782 protein tyrosine kinase binding
IEA
GO_REF:0000107 		ACCEPT
Summary: Cbl binds activated tyrosine kinases (RTKs and SRC-family) through its TKB domain to target them for ubiquitination; a core, mechanistically central interaction MF.
Reason: Core adaptor MF — recognition of the tyrosine-kinase substrates Cbl downregulates.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.
GO:0005794 Golgi apparatus
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
Reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0005829 cytosol
ISO
GO_REF:0000119 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005886 plasma membrane
ISO
GO_REF:0000119 		ACCEPT
Summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
Reason: Site where Cbl engages activated membrane receptors; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005929 cilium
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
Reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0006511 ubiquitin-dependent protein catabolic process
ISO
GO_REF:0000119 		ACCEPT
Summary: Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).
Reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0016567 protein ubiquitination
ISO
GO_REF:0000119 		ACCEPT
Summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
Reason: Direct experimental annotation of Cbl's core ubiquitination process.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0017124 SH3 domain binding
ISO
GO_REF:0000119 		MARK AS OVER ANNOTATED
Summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
Reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
ISO
GO_REF:0000119 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0043066 negative regulation of apoptotic process
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
Reason: Pleiotropic survival-signaling outcome; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.
GO:0046875 ephrin receptor binding
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
Reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Receptor tyrosine kinases (RTKs)
GO:0048260 positive regulation of receptor-mediated endocytosis
ISO
GO_REF:0000119 		ACCEPT
Summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
Reason: Cbl actively drives receptor internalization — core downregulation mechanism.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0050821 protein stabilization
ISO
GO_REF:0000119 		MARK AS OVER ANNOTATED
Summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
Reason: Runs counter to Cbl's degradative role; likely over-annotation.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0050860 negative regulation of T cell receptor signaling pathway
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
Reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0050868 negative regulation of T cell activation
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
Reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Phospho-Cbl recruits PI3K (e.g. Tyr-731 form in osteoclasts) promoting PI3K/AKT signaling; a context-specific positive role distinct from its main negative-regulator function.
Reason: Context-specific PI3K/AKT-promoting role; downstream, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
GO:0061630 ubiquitin protein ligase activity
ISO
GO_REF:0000119 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0070534 protein K63-linked ubiquitination
ISO
GO_REF:0000119 		MODIFY
Summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
Reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
Proposed replacements: protein ubiquitination
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0097229 sperm end piece
ISO
GO_REF:0000119 		KEEP AS NON CORE
Summary: Sperm end-piece localization (ISO only) is a highly tissue-specific finding unrelated to Cbl's core signaling-attenuation role.
Reason: Tissue-specific ISO localization; peripheral, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0000209 protein polyubiquitination
ISO
GO_REF:0000096 		ACCEPT
Summary: Cbl multi/poly-ubiquitinates activated RTKs (e.g. CSF1R multiubiquitination), a documented degradative outcome of its ligase activity.
Reason: Specific, correct ubiquitin-chain type produced by Cbl on receptor substrates.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0005925 focal adhesion
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Focal-adhesion localization (IEA/ISO) fits Cbl's roles in adhesion/cytoskeletal signaling; a context-specific site rather than a core compartment.
Reason: Context-specific adhesion-site localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0006513 protein monoubiquitination
ISO
GO_REF:0000096 		ACCEPT
Summary: Cbl also monoubiquitinates receptors, a recognized signal for endocytic sorting; a valid specific ubiquitination outcome of Cbl.
Reason: Documented mono-ubiquitination activity supporting receptor internalization.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0017124 SH3 domain binding
ISO
GO_REF:0000096 		MARK AS OVER ANNOTATED
Summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
Reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0019901 protein kinase binding
ISO
GO_REF:0000096 		MARK AS OVER ANNOTATED
Summary: Redundant generic kinase-binding term superseded by the more specific protein/receptor tyrosine kinase binding annotations that describe Cbl's actual substrate recognition.
Reason: Generic and redundant with the specific tyrosine-kinase-binding MFs.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0030424 axon
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Axonal localization (IEA/ISO) is a neuronal-context site consistent with Eph-receptor regulation; not a core compartment for the E3/adaptor function.
Reason: Neuronal-context localization; specialized, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0030426 growth cone
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Growth-cone localization (IEA/ISO) reflects neuronal/cytoskeletal context (e.g. Eph signaling); peripheral specialized localization.
Reason: Neuronal context localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0036312 phosphatidylinositol 3-kinase regulatory subunit binding
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Phospho-Cbl interacts with PIK3R1 to recruit PI3K (UniProt SUBUNIT); a genuine partner interaction supporting PI3K coupling but downstream of Cbl's core E3 role.
Reason: Documented PIK3R1 interaction; secondary/effector partner binding, not core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
GO:0043066 negative regulation of apoptotic process
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
Reason: Pleiotropic survival-signaling outcome; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.
GO:0048471 perinuclear region of cytoplasm
ISO
GO_REF:0000096 		KEEP AS NON CORE
Summary: Perinuclear localization (IEA/ISO) is consistent with endosomal/recycling trafficking compartments; a sub-cytoplasmic refinement, non-core.
Reason: Sub-cytoplasmic trafficking-compartment localization; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0051865 protein autoubiquitination
ISO
GO_REF:0000096 		ACCEPT
Summary: Cbl undergoes autoubiquitination (it is itself ubiquitinated leading to proteasomal turnover, per UniProt PTM), a genuine regulatory activity of the RING ligase.
Reason: Self-ubiquitination is a documented PTM/activity consistent with RING E3 function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0061630 ubiquitin protein ligase activity
ISO
GO_REF:0000096 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:1990782 protein tyrosine kinase binding
ISO
GO_REF:0000096 		ACCEPT
Summary: Cbl binds activated tyrosine kinases (RTKs and SRC-family) through its TKB domain to target them for ubiquitination; a core, mechanistically central interaction MF.
Reason: Core adaptor MF — recognition of the tyrosine-kinase substrates Cbl downregulates.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.
GO:0061630 ubiquitin protein ligase activity
TAS
Reactome:R-MMU-9763892 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0050821 protein stabilization
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
Reason: Runs counter to Cbl's degradative role; likely over-annotation.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0050860 negative regulation of T cell receptor signaling pathway
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
Reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0050868 negative regulation of T cell activation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
Reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
GO:0061630 ubiquitin protein ligase activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0070534 protein K63-linked ubiquitination
ISS
GO_REF:0000024 		MODIFY
Summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
Reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
Proposed replacements: protein ubiquitination
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IMP
PMID:12754251
Cbl-mediated ubiquitinylation is required for lysosomal sort... 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0061630 ubiquitin protein ligase activity
IMP
PMID:15962011
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epiderma... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0005886 plasma membrane
IDA
PMID:15383614
c-Cbl directs EGF receptors into an endocytic pathway that i... 		ACCEPT
Summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
Reason: Site where Cbl engages activated membrane receptors; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0016567 protein ubiquitination
ISO
PMID:11823423
A mutant EGF-receptor defective in ubiquitylation and endocy... 		ACCEPT
Summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
Reason: Direct experimental annotation of Cbl's core ubiquitination process.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IGI
PMID:11823423
A mutant EGF-receptor defective in ubiquitylation and endocy... 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0061630 ubiquitin protein ligase activity
IGI
PMID:11823423
A mutant EGF-receptor defective in ubiquitylation and endocy... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0061630 ubiquitin protein ligase activity
IMP
PMID:12754251
Cbl-mediated ubiquitinylation is required for lysosomal sort... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0070086 ubiquitin-dependent endocytosis
ISO
PMID:11823423
A mutant EGF-receptor defective in ubiquitylation and endocy... 		ACCEPT
Summary: Core BP: Cbl ubiquitination of activated receptors couples them to the endocytic machinery for internalization (IMP:MGI), the adaptor/trafficking arm of its function.
Reason: Directly links Cbl ubiquitination to receptor endocytosis; core trafficking role.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0006511 ubiquitin-dependent protein catabolic process
IMP
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).
Reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0016567 protein ubiquitination
IDA
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
Reason: Direct experimental annotation of Cbl's core ubiquitination process.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IDA
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
IMP
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0061630 ubiquitin protein ligase activity
IDA
PMID:15383614
c-Cbl directs EGF receptors into an endocytic pathway that i... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0061630 ubiquitin protein ligase activity
IDA
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0061630 ubiquitin protein ligase activity
IMP
PMID:23457600
Berberine inhibits proliferation and down-regulates epiderma... 		ACCEPT
Summary: Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).
Reason: Best-supported core molecular function with direct experimental evidence.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0070086 ubiquitin-dependent endocytosis
IMP
PMID:15383614
c-Cbl directs EGF receptors into an endocytic pathway that i... 		ACCEPT
Summary: Core BP: Cbl ubiquitination of activated receptors couples them to the endocytic machinery for internalization (IMP:MGI), the adaptor/trafficking arm of its function.
Reason: Directly links Cbl ubiquitination to receptor endocytosis; core trafficking role.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0016600 flotillin complex
IDA
PMID:11001060
CAP defines a second signalling pathway required for insulin... 		KEEP AS NON CORE
Summary: Association with the flotillin complex (IDA:BHF-UCL) reflects membrane-microdomain/endocytic context; a real but peripheral complex membership.
Reason: Specific microdomain complex membership; peripheral to core function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0005515 protein binding
IPI
PMID:9447983
A novel, multifuntional c-Cbl binding protein in insulin rec... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005829 cytosol
TAS
Reactome:R-MMU-9680646 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9680706 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9682158 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9682182 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9763891 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9763892 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0005829 cytosol
TAS
Reactome:R-MMU-9817994 		ACCEPT
Summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
Reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
GO:0016567 protein ubiquitination
ISS
GO_REF:0000024 		ACCEPT
Summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
Reason: Direct experimental annotation of Cbl's core ubiquitination process.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
GO:0032487 regulation of Rap protein signal transduction
IMP
PMID:12671687
Negative regulation of Rap1 activation by the Cbl E3 ubiquit... 		KEEP AS NON CORE
Summary: Cbl modulates Rap GTPase signaling (IMP), plausibly via C3G/CrkL adaptor complexes; a specific but downstream signaling-regulation role.
Reason: Specific downstream small-GTPase signaling regulation; non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.
GO:0005794 Golgi apparatus
IDA
PMID:29237719
IFT20 modulates ciliary PDGFRα signaling by regulating the s... 		KEEP AS NON CORE
Summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
Reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:0005929 cilium
IDA
PMID:29237719
IFT20 modulates ciliary PDGFRα signaling by regulating the s... 		KEEP AS NON CORE
Summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
Reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
GO:2000583 regulation of platelet-derived growth factor receptor-alpha signaling pathway
IMP
PMID:29237719
IFT20 modulates ciliary PDGFRα signaling by regulating the s... 		ACCEPT
Summary: Cbl (with Cbl-b) provides feedback inhibition of ciliary PDGFRA signaling via PDGFRA ubiquitination and internalization (IMP:UniProtKB; PubMed:29237719).
Reason: Specific, experimentally supported PDGFRA negative-feedback role; mirrors UniProt FUNCTION.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-family ubiquitination of activated RTKs (EGFR paradigm) is a central, experimentally grounded function that links phosphorylation-dependent recognition to endosomal sorting and receptor downregulation.
GO:0005515 protein binding
IPI
PMID:8551236
Association of tyrosine protein kinase Zap-70 with the proto... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:21830225
SH3KBP1-binding protein 1 prevents epidermal growth factor r... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0006511 ubiquitin-dependent protein catabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).
Reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway
ISS
GO_REF:0000024 		ACCEPT
Summary: Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).
Reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.
GO:0048260 positive regulation of receptor-mediated endocytosis
ISS
GO_REF:0000024 		ACCEPT
Summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
Reason: Cbl actively drives receptor internalization — core downregulation mechanism.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
GO:0005515 protein binding
IPI
PMID:11152963
SETA is a multifunctional adapter protein with three SH3 dom... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0005515 protein binding
IPI
PMID:16455755
Spatial and temporal regulation of GLUT4 translocation by fl... 		MARK AS OVER ANNOTATED
Summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
Reason: Generic protein binding conveys no functional information; always over-annotated.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).
GO:0046875 ephrin receptor binding
IPI
PMID:18034775
Ligand binding induces Cbl-dependent EphB1 receptor degradat... 		KEEP AS NON CORE
Summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
Reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Receptor tyrosine kinases (RTKs)
GO:0006468 protein phosphorylation
ISS
GO_REF:0000024 		REMOVE
Summary: Cbl is a ubiquitin ligase, not a protein kinase; it is phosphorylated BY kinases but does not catalyze protein phosphorylation. This ISS annotation reverses the direction of the modification and is incorrect.
Reason: Cbl has no kinase activity; annotation contradicts its biochemistry (it is a substrate, not a kinase).
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
Cbl-family proteins are **RING-type E3 ligases**, meaning they **do not form a catalytic ubiquitin thioester intermediate**; instead, they bring an **E2~ubiquitin conjugate** into proximity with the substrate to enable transfer.
GO:0045453 bone resorption
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Cbl is required for osteoclastic bone resorption (ISS; UniProt FUNCTION); an important tissue-level physiological role downstream of its signaling functions.
Reason: Tissue-level osteoclast physiology; downstream, non-core.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
In intestine, c-Cbl and Cbl-b are partly redundant
GO:0017124 SH3 domain binding
IPI
PMID:9447983
A novel, multifuntional c-Cbl binding protein in insulin rec... 		MARK AS OVER ANNOTATED
Summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
Reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
Supporting Evidence:
UniProt:P22682
FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
file:mouse/Cbl/Cbl-deep-research-falcon.md
**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).

Core Functions

Transfers ubiquitin to activated receptor tyrosine kinases and signaling substrates to attenuate signaling and promote receptor downregulation.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
protein ubiquitination negative regulation of epidermal growth factor receptor signaling pathway
Cellular Locations:
cytosol plasma membrane
Supporting Evidence:
  • UniProt:P22682
    FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
  • file:mouse/Cbl/Cbl-deep-research-falcon.md
    c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).

The TKB/phosphotyrosine-binding region recognizes activated receptor tyrosine kinases, positioning the RING E3 ligase domain for substrate ubiquitination.

Molecular Function:
receptor tyrosine kinase binding
Directly Involved In:
ubiquitin-dependent endocytosis
Cellular Locations:
cytosol plasma membrane
Supporting Evidence:
  • UniProt:P22682
    FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.
  • file:mouse/Cbl/Cbl-deep-research-falcon.md
    c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000096
Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000119
Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:11001060
CAP defines a second signalling pathway required for insulin-stimulated glucose transport.
PMID:11152963
SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins.
PMID:11823423
A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling.
PMID:12559036
CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl.
PMID:12671687
Negative regulation of Rap1 activation by the Cbl E3 ubiquitin ligase.
PMID:12754251
Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis.
PMID:15383614
c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15.
PMID:15962011
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation.
PMID:16455755
Spatial and temporal regulation of GLUT4 translocation by flotillin-1 and caveolin-3 in skeletal muscle cells.
PMID:18034775
Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway.
PMID:21830225
SH3KBP1-binding protein 1 prevents epidermal growth factor receptor degradation by the interruption of c-Cbl-CIN85 complex.
PMID:23374343
Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation.
PMID:23457600
Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells.
PMID:23799367
Threshold-controlled ubiquitination of the EGFR directs receptor fate.
PMID:24440350
Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.
PMID:27474268
Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation.
PMID:29237719
IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases.
PMID:7657591
Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.
PMID:8551236
Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.
PMID:9447983
A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes.
PMID:9890970
Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase.
Reactome:R-MMU-9680646
Pik3r11:Pik3ca,b,d (Pi3k), Plcg2 (PLCgamma2), Grb2:Sos1, Shc1 (Shc), Ptpn11 (Shp2), Grb2:Gab2, Grb2:Gab3, Grap2 (MONA), Cbl:Grb2, Inpp5d (SHIP1), Inppl1 (SHIP2) bind p-8Y-Csf1r and are activated
Reactome:R-MMU-9680706
Csf1r trans-autophosphorylates on multiple tyrosine residues
Reactome:R-MMU-9682158
Csf1r-associated Plcg2 hydrolyzes phosphatidylcholine yielding choline phosphate and 1,2-diacylglycerol
Reactome:R-MMU-9682182
Csf1r-associated PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate
Reactome:R-MMU-9763891
Src family kinases phosphorylate Cbl in Csf1 dimer:p-Y559-Csf1r dimer:Cbl
Reactome:R-MMU-9763892
p-Y-Cbl autoubiquitinates and multiubiquitinates p-Y-559-Csf12
Reactome:R-MMU-9817994
Csf1 dimer:p-Y559-Csf1r dimer:Fyn,Hck,Src,Yes1 binds Cbl
UniProt:P22682
UniProt record for Cbl (P22682)
file:mouse/Cbl/Cbl-deep-research-falcon.md
Deep research report on Cbl (falcon)

Deep Research

Falcon

(Cbl-deep-research-falcon.md)
Research report: Mouse **Cbl / c-Cbl** (UniProt **P22682**) — functional annotation Falcon Edison Scientific Literature 29 citations 2026-05-03T14:04:56.189304

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Mouse Cbl / c-Cbl (UniProt P22682) — functional annotation

0) Identity verification and scope

The target protein is mouse c-Cbl (gene: Cbl; UniProt: P22682), a member of the CBL-family RING-type E3 ubiquitin ligases. Recent reviews and primary studies consistently describe CBL proteins (c-Cbl, Cbl-b, Cbl-c) as E3 ligases with a conserved N-terminal tyrosine kinase binding domain (TKB/TKBD) and a catalytic RING finger separated by a linker helix region (LHR), matching the UniProt domain expectations for mouse Cbl (Adaptor_Cbl/TKB-related modules). (zutshi2024cblandcblb pages 1-2, nath2024mechanismsofcblmediated pages 1-3, ren2024theroleof pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Ubiquitination and what an E3 ligase does

Ubiquitination is a post-translational modification in which ubiquitin is covalently attached to substrate proteins through an enzymatic cascade (E1 activating enzyme → E2 conjugating enzyme → E3 ligase). Cbl-family proteins are RING-type E3 ligases, meaning they do not form a catalytic ubiquitin thioester intermediate; instead, they bring an E2~ubiquitin conjugate into proximity with the substrate to enable transfer. (nath2024mechanismsofcblmediated pages 1-3)

1.2 Cbl as a “signal- and trafficking-coupled” E3 ligase

Across receptor systems, c-Cbl is best understood as an activation-dependent negative regulator of signaling that couples recognition of phosphotyrosine-containing activated signaling complexes to ubiquitin-dependent downregulation (often routing to lysosomes for receptor degradation) and/or proteasomal degradation of signaling proteins. (ren2024theroleof pages 1-2, duan2003cblmediatedubiquitinylationis pages 1-1, nath2024mechanismsofcblmediated pages 1-3)

1.3 Domain architecture and how it explains function

CBL proteins share a modular architecture:
- TKBD/TKB: a composite domain comprising a 4-helix bundle, EF-hand, and an SH2-like phosphotyrosine-recognition module that mediates binding to phosphorylated targets. (nath2024mechanismsofcblmediated pages 1-3)
- Linker helix region (LHR): a regulatory segment connecting TKBD to the RING; phosphorylation within this region is central to activation. (nath2024mechanismsofcblmediated pages 1-3)
- RING finger: binds E2 enzymes and is required for ubiquitin transfer to substrates. (ren2024theroleof pages 1-2, duan2003cblmediatedubiquitinylationis pages 1-1)
- C-terminal interaction motifs: proline-rich and ubiquitin-associated features (prominent in c-Cbl and Cbl-b) support assembly of signaling complexes and ubiquitin binding. (zutshi2024cblandcblb pages 1-2, nath2024mechanismsofcblmediated pages 1-3)

A representative schematic of domain architecture and ubiquitin-transfer mechanism is shown in Nath & Isakov 2024 (Life) (Figure 1). (nath2024mechanismsofcblmediated media 211be9ea)

2) Primary biochemical function: reaction catalyzed and substrate specificity

2.1 Reaction catalyzed

c-Cbl catalyzes transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context). (ren2024theroleof pages 1-2, nath2024mechanismsofcblmediated pages 1-3)

2.2 Substrate recognition logic (“specificity”)

Cbl’s substrate specificity is largely context- and phosphorylation-dependent:
- Direct recognition via TKB/TKBD binding to phosphotyrosines on activated receptors/proteins. (nath2024mechanismsofcblmediated pages 1-3, duan2003cblmediatedubiquitinylationis pages 1-1)
- Indirect recruitment through adaptors (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions). (duan2003cblmediatedubiquitinylationis pages 1-1)

2.3 Representative substrates/targets (well-supported)

Receptor tyrosine kinases (RTKs)
- EGFR is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient lysosomal sorting/degradation of EGFR after ligand stimulation; direct binding can occur via EGFR pY1045 to the Cbl TKB domain, with an alternative Grb2-mediated route. (duan2003cblmediatedubiquitinylationis pages 1-1)
- Newer mechanistic refinement (2023): Cbl and Cbl-b can regulate EGFR using distinct interaction modes, where Cbl-b preferentially binds EGFR pY1045, while Cbl relies mainly on Grb2-dependent recruitment in the tested context. (pinillamacua2023cblandcblb pages 1-2)

Immune signaling proteins (T/NK cell context)
A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including TCR/CD3 subunits, Src-family kinases Fyn and Lck, the adaptor LAT, and other pathway components in T and NK cells. (nath2024mechanismsofcblmediated pages 1-3)

Limitations: The retrieved 2023–2024 sources used here describe E2 recruitment conceptually through the RING domain but do not consistently specify a single dominant E2 partner for c-Cbl in vivo; therefore, E2 partner specificity is not asserted beyond “RING-mediated E2 recruitment.” (nath2024mechanismsofcblmediated pages 1-3, ren2024theroleof pages 1-2)

3) Regulation and activation (recent mechanistic themes)

3.1 Autoinhibition and phosphorylation-dependent activation

Cbl is regulated by autoinhibition, in which the inactive conformation restricts catalytic function until receptor engagement and phosphorylation relieve inhibition. A conserved linker-region regulatory tyrosine (classically discussed as Tyr371 in c-Cbl) is emphasized as a key activation switch in mechanistic summaries. (liyasova2015molecularpathwayscbl pages 1-2)

3.2 Context-specific regulation in innate immunity (2024 primary mouse study)

A 2024 PNAS study defined a mechanistic module in macrophages: CLR (Dectin-1/2) → Syk → BLNK phosphorylation leads to BLNK association with c-Cbl, which inhibits Fyn-mediated phosphorylation of c-Cbl (including phosphorylation at Y737 as reported) and reduces downstream cytoskeletal/migratory outputs. (yang2024blnknegativelyregulates pages 7-8, yang2024blnknegativelyregulates pages 1-2)

4) Cellular localization and where c-Cbl acts

c-Cbl is best viewed as a cytosolic adaptor/E3 that is recruited to activated plasma-membrane signaling complexes and subsequently to endocytic/endosomal trafficking sites, where it ubiquitinates receptors and associated proteins to direct trafficking fate:
- In the EGFR system, Cbl-dependent ubiquitination is required for sorting from early endosomes toward lysosomal degradation (a key step distinct from initial endocytosis). (duan2003cblmediatedubiquitinylationis pages 1-1)
- In macrophages responding to fungal ligands, c-Cbl is linked to F-actin/podosome-associated structures and PI3K-associated cytoskeletal remodeling required for migration. (yang2024blnknegativelyregulates pages 6-7)

5) Pathways and biological processes (with 2023–2024 emphasis)

5.1 RTK signaling attenuation and receptor trafficking

Cbl-family ubiquitination of activated RTKs (EGFR paradigm) is a central, experimentally grounded function that links phosphorylation-dependent recognition to endosomal sorting and receptor downregulation. (duan2003cblmediatedubiquitinylationis pages 1-1, pinillamacua2023cblandcblb pages 1-2)

5.2 Intestinal epithelial stem cell (ISC) maintenance (mouse in vivo; 2024)

A 2024 iScience mouse study concluded that c-Cbl and Cbl-b have overlapping essential roles in maintaining intestinal epithelial stem cells:
- Whole-body double knockout is embryonic lethal (functional redundancy). (zutshi2024cblandcblb pages 15-16)
- In an Lgr5+ ISC-specific inducible double knockout, loss of Cbl/Cbl-b caused a rapid decrease in Lgr5+ ISCs with an increase in Lgr5-low transit-amplifying-like cells, increased crypt proliferation/fission, and reduced Paneth cells, but without long-term adenoma development in that system. (zutshi2024cblandcblb pages 15-16)
These phenotypes are consistent with Cbl-family control of growth-factor/cytokine signaling intensity (e.g., Akt–mTOR pathway readouts reported in the study). (zutshi2024cblandcblb pages 15-16)

5.3 Innate antifungal immunity via macrophage migration (mouse in vivo; 2024)

The 2024 PNAS study supports a role for c-Cbl in macrophage podosome organization and migration, affecting host defense:
- Myeloid c-Cbl-deficient mice (Lyz2Cre/+ c-Cbl fl/fl) had increased susceptibility to systemic Candida albicans infection and reduced infiltration of Ly6C+ macrophages into kidneys. (yang2024blnknegativelyregulates pages 6-7)
- Mechanistically, BLNK modulated c-Cbl phosphorylation and PI3K-associated actin remodeling, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment. (yang2024blnknegativelyregulates pages 7-8)

6) Recent developments (prioritizing 2023–2024)

6.1 EGFR regulation is not purely “redundant Cbl vs Cbl-b” (2023)

A 2023 study showed that even for a canonical substrate like EGFR, Cbl and Cbl-b can operate independently via different receptor-binding modes, and the impact of E3-dead mutants can be cell-context dependent (e.g., relative abundance of endogenous Cbl-b). (pinillamacua2023cblandcblb pages 1-2)

6.2 New in vivo biology: stem-cell and infection contexts (2024)

Two 2024 mouse studies extend functional annotation beyond classic RTK/immune-proximal signaling:
- Epithelial stem cell maintenance (intestinal crypt biology). (zutshi2024cblandcblb pages 15-16)
- CLR-driven innate immunity and migration during fungal infection. (yang2024blnknegativelyregulates pages 6-7)

A 2024 EMBO Molecular Medicine study connected PD-1/LAG-3 “dysfunction” signatures to negative regulation of the TCR signalosome and enrichment in ubiquitin ligase pathways, highlighting CBL-family ligases as actionable nodes. (chocarro2024pd1lag3cosignalingprofiling pages 1-2)

7) Current applications and real-world implementations

7.1 Immuno-oncology targeting of the CBL pathway (mostly CBL-B; mechanistic relevance to c-Cbl)

The strongest “real-world implementation” currently is pharmacologic targeting of CBL-family regulation in T cells, mainly via CBL-B inhibition as a means to increase T-cell activation.

In preclinical mouse studies reported in EMBO Molecular Medicine (2024), the authors tested anti-PD-1 + anti-LAG-3 with a CBL-B inhibitor in a Lacun3 lung adenocarcinoma model described as refractory to immunotherapy. They report dosing schedules (CBL-B inhibitor 10–30 mg/kg; antibodies 100 µg i.p. schedules) and claim that triple therapy “more than tripled survival” in a tested regimen; they also report n = 6 mice/group for in vivo cohorts. (chocarro2024pd1lag3cosignalingprofiling pages 10-12)

7.2 Clinical trials (CBL-B inhibitors)

ClinicalTrials.gov includes a first-in-human, multicenter Phase 1a/1b study of NX-1607 (a CBL-B inhibitor) in adults with advanced malignancies:
- Identifier: NCT05107674 (https://clinicaltrials.gov/study/NCT05107674)
- Sponsor: Nurix Therapeutics, Inc.
- Start date: 2021-09-29
- Status: Recruiting
- Enrollment: 345
- Design: oral NX-1607 monotherapy and combination arms (including paclitaxel), with primary endpoints focused on safety/MTD and Phase 1b ORR. (NCT05107674 chunk 1)

The EMBO Molecular Medicine paper also explicitly references ongoing clinical evaluation of CBL-B inhibitors including NCT05662397 (https://clinicaltrials.gov/study/NCT05662397) in the context of combination strategies. (chocarro2024pd1lag3cosignalingprofiling pages 10-12)

Important scope note: These programs are primarily CBL-B-directed; nevertheless, the mechanistic foundation (CBL-family E3 ligases controlling phosphotyrosine-driven signaling thresholds) is shared with c-Cbl/Cbl and informs functional annotation and pathway-level applications. (ren2024theroleof pages 1-2, nath2024mechanismsofcblmediated pages 1-3, chocarro2024pd1lag3cosignalingprofiling pages 1-2)

8) Disease relevance and quantitative statistics from recent mechanistic summaries

Although the present report focuses on mouse c-Cbl, recent mechanistic summaries emphasize that CBL mutations are recurrent in hematologic malignancies and motivate therapeutic interest in CBL-pathway modulation. A recent mechanistic account reports that CBL mutations occur in ~5% of myeloid leukemias overall, and in 15–20% of JMML and ~15% of CMML. (tench2026targetingcblubiquitin pages 1-5)

9) Expert interpretation (evidence-based synthesis)

The best-supported “core functional annotation” for mouse c-Cbl (P22682) is:
1) A phosphorylation-activated RING E3 ubiquitin ligase that recognizes activated signaling proteins via its TKBD and ubiquitinates them via RING-mediated E2 recruitment. (nath2024mechanismsofcblmediated pages 1-3, ren2024theroleof pages 1-2)
2) A central negative-feedback regulator of receptor signaling by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype). (duan2003cblmediatedubiquitinylationis pages 1-1)
3) A context-dependent signaling rheostat in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense. (yang2024blnknegativelyregulates pages 7-8, yang2024blnknegativelyregulates pages 6-7)
4) Functionally redundant with Cbl-b in specific tissues such that combined loss reveals essential roles in tissue homeostasis (intestinal stem cell maintenance). (zutshi2024cblandcblb pages 15-16)

Evidence map table

Aspect Key evidence/findings (concise) Primary citations (pqac ids)
Reaction/Function Mouse c-Cbl (Cbl; UniProt P22682) matches the canonical CBL-family RING-type E3 ubiquitin ligase/adaptor: it recognizes phosphotyrosine-containing targets through its TKB/TKBD and recruits E2 enzymes through its RING domain to catalyze mono- or polyubiquitination, typically promoting receptor downregulation, endosomal sorting, lysosomal degradation, or altered signaling output. A classic well-established function is negative regulation of activated RTKs such as EGFR. (ren2024theroleof pages 1-2, pinillamacua2023cblandcblb pages 1-2, duan2003cblmediatedubiquitinylationis pages 1-1, nath2024mechanismsofcblmediated pages 1-3)
Key domains Core domain architecture is conserved and matches UniProt/domain annotations: N-terminal TKBD/TKB composed of a 4-helix bundle, EF-hand-like region, and SH2-like phosphotyrosine-recognition module; linker helix region (LHR); catalytic RING finger; plus C-terminal proline-rich region and UBA/leucine zipper features in c-Cbl/CBL-b. (zutshi2024cblandcblb pages 1-2, nath2024mechanismsofcblmediated pages 1-3, ren2024theroleof pages 1-2, nath2024mechanismsofcblmediated media 211be9ea)
Regulation c-Cbl is autoinhibited in its basal state; activation occurs after recruitment to active tyrosine kinases and phosphorylation of the linker-region regulatory tyrosine (classically Tyr371 in c-Cbl), which relieves autoinhibition and enables productive ubiquitin transfer. Adaptor binding can also modulate activation, and recent work highlights BLNK/Fyn/Syk control of c-Cbl phosphorylation in macrophages. (tench2026targetingcblubiquitin pages 16-19, liyasova2015molecularpathwayscbl pages 1-2, yang2024blnknegativelyregulates pages 7-8, yang2024blnknegativelyregulates pages 1-2)
Representative substrates Best-established substrates/targets include activated EGFR/RTKs; immune signaling proteins such as TCR/CD3 subunits, ZAP70-associated complexes, Src-family kinases Fyn and Lck, LAT, and C3G are also described for Cbl-family signaling control. For EGFR specifically, Cbl and Cbl-b can bind by distinct mechanisms, with c-Cbl relying mainly on Grb2-dependent recruitment in some cell contexts. (pinillamacua2023cblandcblb pages 1-2, duan2003cblmediatedubiquitinylationis pages 1-1, nath2024mechanismsofcblmediated pages 1-3)
Pathways/cell types c-Cbl is most firmly placed in RTK downregulation and immune receptor signaling. Established settings include EGFR trafficking/signaling, TCR/NK-cell signaling, cytokine/Src-family kinase pathways, intestinal epithelial stem-cell homeostasis, and CLR/Syk/Fyn/PI3K signaling in macrophages responding to fungal ligands. (ren2024theroleof pages 1-2, nath2024mechanismsofcblmediated pages 1-3, yang2024blnknegativelyregulates pages 7-8, zutshi2024cblandcblb pages 15-16)
Cellular localization Functional activity is context dependent: c-Cbl is cytosolic/adaptor-like at baseline, then recruited to activated membrane receptor complexes, clathrin-associated/endosomal trafficking machinery, and signaling assemblies where it promotes receptor ubiquitination, internalization, intraluminal vesicle sorting, and lysosomal targeting. In macrophages it also associates with F-actin/podosome-related structures during migration signaling. (pinillamacua2023cblandcblb pages 1-2, duan2003cblmediatedubiquitinylationis pages 1-1, yang2024blnknegativelyregulates pages 7-8, yang2024blnknegativelyregulates pages 6-7)
Mouse phenotypes 2024 iScience & 2024 PNAS In intestine, c-Cbl and Cbl-b are partly redundant: ISC-specific inducible double loss caused rapid depletion of Lgr5+ stem cells, increase in Lgr5-low transit-amplifying-like cells, increased crypt proliferation/fission, altered differentiation, and reduced Paneth cells; whole-body double knockout is embryonic lethal. In myeloid cells, c-Cbl promoted macrophage migration/podosome organization and kidney Ly6C+ macrophage infiltration during Candida infection; myeloid c-Cbl deficiency increased susceptibility to systemic candidiasis. (zutshi2024cblandcblb pages 15-16, yang2024blnknegativelyregulates pages 6-7, yang2024blnknegativelyregulates pages 1-2)
Translational/therapeutic angles 2024 EMBO Mol Med & clinical trials A 2024 EMBO Mol Med study identified CBL-family ligases as immunotherapy-relevant nodes downstream of PD-1/LAG-3 dysfunction programs; combined checkpoint blockade plus CBL-B inhibition showed significant antitumor activity in a refractory mouse lung cancer model, with reports that triple therapy more than tripled survival in one regimen and required CD8 T cells. Clinically, CBL-B-directed agents are already in early trials, including NX-1607 (NCT05107674; phase 1, recruiting; planned enrollment 345) and HST-1011 (NCT05662397; phase 1/2, active not recruiting; enrollment 77), illustrating translational exploitation of the broader CBL pathway even though these programs mainly target CBL-B rather than c-Cbl itself. (chocarro2024pd1lag3cosignalingprofiling pages 10-12, chocarro2024pd1lag3cosignalingprofiling pages 10-10, chocarro2024pd1lag3cosignalingprofiling pages 1-2)

Table: This table summarizes the core functional annotation of mouse c-Cbl (Cbl; UniProt P22682), including its biochemical role, domains, regulation, representative substrates, localization, mouse phenotypes, and translational relevance. It is useful as a compact evidence map linking recent 2023-2024 findings to established mechanistic literature.

Visual evidence

A domain-and-mechanism schematic for CBL-family ubiquitination (Figure 1) is available from Nath & Isakov 2024 (Life). (nath2024mechanismsofcblmediated media 211be9ea)

Key 2023–2024 sources used (with URLs and publication dates)

  • Pinilla-Macua I, Sorkin A. Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes. Molecular Biology of the Cell. 2023-12. https://doi.org/10.1091/mbc.e23-02-0058 (pinillamacua2023cblandcblb pages 1-2)
  • Zutshi N, et al. Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance. iScience. 2024-05. https://doi.org/10.1016/j.isci.2024.109912 (zutshi2024cblandcblb pages 15-16)
  • Yang Y-H, et al. BLNK negatively regulates innate antifungal immunity through inhibiting c-Cbl-mediated macrophage migration. PNAS. 2024-10. https://doi.org/10.1073/pnas.2400920121 (yang2024blnknegativelyregulates pages 6-7)
  • Nath PR, Isakov N. Mechanisms of Cbl-mediated ubiquitination of proteins in T and Natural Killer Cells and Effects on Immune Cell Functions. Life. 2024-12. https://doi.org/10.3390/life14121592 (nath2024mechanismsofcblmediated pages 1-3)
  • Ren J, et al. The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies. Frontiers in Pharmacology. 2024-07. https://doi.org/10.3389/fphar.2024.1432545 (ren2024theroleof pages 1-2)
  • Chocarro L, et al. PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets. EMBO Molecular Medicine. 2024-07. https://doi.org/10.1038/s44321-024-00098-y (chocarro2024pd1lag3cosignalingprofiling pages 10-12)

Notes on evidence gaps

  • UniProt accession-level mapping (P22682 explicitly) was not directly stated in the retrieved papers’ excerpts; identity was validated through consistent matching of organism (mouse), naming (c-Cbl/Cbl), and characteristic domain architecture/function of CBL-family E3 ligases. (zutshi2024cblandcblb pages 1-2, nath2024mechanismsofcblmediated pages 1-3)
  • Several mechanistic details (e.g., dominant E2 partners for c-Cbl in vivo; chain-type preferences in specific contexts) are not explicitly provided in the 2023–2024 sources retrieved here and would require targeted biochemical literature retrieval beyond the current corpus. (nath2024mechanismsofcblmediated pages 1-3, ren2024theroleof pages 1-2)

References

  1. (zutshi2024cblandcblb pages 1-2): Neha Zutshi, Bhopal Mohapatra, Pinaki Mondal, Wei An, Benjamin T. Goetz, Shuo Wang, Sicong Li, Matthew D. Storck, David F. Mercer, Adrian Black, Sarah P. Thayer, Jennifer D. Black, Chi Lin, Vimla Band, and Hamid Band. Cbl and cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance. iScience, May 2024. URL: https://doi.org/10.1016/j.isci.2024.109912, doi:10.1016/j.isci.2024.109912. This article has 5 citations and is from a peer-reviewed journal.

  2. (nath2024mechanismsofcblmediated pages 1-3): Pulak Ranjan Nath and Noah Isakov. Mechanisms of cbl-mediated ubiquitination of proteins in t and natural killer cells and effects on immune cell functions. Life, 14:1592, Dec 2024. URL: https://doi.org/10.3390/life14121592, doi:10.3390/life14121592. This article has 2 citations.

  3. (ren2024theroleof pages 1-2): Jiaqi Ren, Linlin Lv, Xufeng Tao, Xiaohan Zhai, Xuyang Chen, Hao Yu, Xinya Zhao, Xin Kong, Zhan Yu, Deshi Dong, and Jing Liu. The role of cbl family ubiquitin ligases in cancer progression and therapeutic strategies. Frontiers in Pharmacology, Jul 2024. URL: https://doi.org/10.3389/fphar.2024.1432545, doi:10.3389/fphar.2024.1432545. This article has 12 citations.

  4. (duan2003cblmediatedubiquitinylationis pages 1-1): Lei Duan, Yuko Miura, Manjari Dimri, Biswanath Majumder, Ingrid L. Dodge, Alagarsamy L. Reddi, Amiya Ghosh, Norvin Fernandes, Pengcheng Zhou, Karen Mullane-Robinson, Navin Rao, Stephen Donoghue, Rick A. Rogers, David Bowtell, Mayumi Naramura, Hua Gu, Vimla Band, and Hamid Band. Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis*. Journal of Biological Chemistry, 278:28950-28960, Aug 2003. URL: https://doi.org/10.1074/jbc.m304474200, doi:10.1074/jbc.m304474200. This article has 169 citations and is from a domain leading peer-reviewed journal.

  5. (nath2024mechanismsofcblmediated media 211be9ea): Pulak Ranjan Nath and Noah Isakov. Mechanisms of cbl-mediated ubiquitination of proteins in t and natural killer cells and effects on immune cell functions. Life, 14:1592, Dec 2024. URL: https://doi.org/10.3390/life14121592, doi:10.3390/life14121592. This article has 2 citations.

  6. (pinillamacua2023cblandcblb pages 1-2): Itziar Pinilla-Macua and Alexander Sorkin. Cbl and cbl-b independently regulate egfr through distinct receptor interaction modes. Molecular Biology of the Cell, Dec 2023. URL: https://doi.org/10.1091/mbc.e23-02-0058, doi:10.1091/mbc.e23-02-0058. This article has 26 citations and is from a domain leading peer-reviewed journal.

  7. (liyasova2015molecularpathwayscbl pages 1-2): Mariya S. Liyasova, Ke Ma, and Stanley Lipkowitz. Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity—opportunities for cancer treatment. Clinical Cancer Research, 21:1789-1794, Apr 2015. URL: https://doi.org/10.1158/1078-0432.ccr-13-2490, doi:10.1158/1078-0432.ccr-13-2490. This article has 86 citations and is from a highest quality peer-reviewed journal.

  8. (yang2024blnknegativelyregulates pages 7-8): Yi-Heng Yang, Ke-Fang Xie, Shuai Yang, Huan Wang, Hui-Hui Ma, Min Zhou, Zhong-Wei Wang, Yebo Gu, and Xin-Ming Jia. Blnk negatively regulates innate antifungal immunity through inhibiting c-cbl-mediated macrophage migration. Proceedings of the National Academy of Sciences of the United States of America, Oct 2024. URL: https://doi.org/10.1073/pnas.2400920121, doi:10.1073/pnas.2400920121. This article has 8 citations and is from a highest quality peer-reviewed journal.

  9. (yang2024blnknegativelyregulates pages 1-2): Yi-Heng Yang, Ke-Fang Xie, Shuai Yang, Huan Wang, Hui-Hui Ma, Min Zhou, Zhong-Wei Wang, Yebo Gu, and Xin-Ming Jia. Blnk negatively regulates innate antifungal immunity through inhibiting c-cbl-mediated macrophage migration. Proceedings of the National Academy of Sciences of the United States of America, Oct 2024. URL: https://doi.org/10.1073/pnas.2400920121, doi:10.1073/pnas.2400920121. This article has 8 citations and is from a highest quality peer-reviewed journal.

  10. (yang2024blnknegativelyregulates pages 6-7): Yi-Heng Yang, Ke-Fang Xie, Shuai Yang, Huan Wang, Hui-Hui Ma, Min Zhou, Zhong-Wei Wang, Yebo Gu, and Xin-Ming Jia. Blnk negatively regulates innate antifungal immunity through inhibiting c-cbl-mediated macrophage migration. Proceedings of the National Academy of Sciences of the United States of America, Oct 2024. URL: https://doi.org/10.1073/pnas.2400920121, doi:10.1073/pnas.2400920121. This article has 8 citations and is from a highest quality peer-reviewed journal.

  11. (zutshi2024cblandcblb pages 15-16): Neha Zutshi, Bhopal Mohapatra, Pinaki Mondal, Wei An, Benjamin T. Goetz, Shuo Wang, Sicong Li, Matthew D. Storck, David F. Mercer, Adrian Black, Sarah P. Thayer, Jennifer D. Black, Chi Lin, Vimla Band, and Hamid Band. Cbl and cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance. iScience, May 2024. URL: https://doi.org/10.1016/j.isci.2024.109912, doi:10.1016/j.isci.2024.109912. This article has 5 citations and is from a peer-reviewed journal.

  12. (chocarro2024pd1lag3cosignalingprofiling pages 1-2): Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, and David Escors. Pd-1/lag-3 co-signaling profiling uncovers cbl ubiquitin ligases as key immunotherapy targets. EMBO Molecular Medicine, 16:1791-1816, Jul 2024. URL: https://doi.org/10.1038/s44321-024-00098-y, doi:10.1038/s44321-024-00098-y. This article has 18 citations and is from a highest quality peer-reviewed journal.

  13. (chocarro2024pd1lag3cosignalingprofiling pages 10-12): Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, and David Escors. Pd-1/lag-3 co-signaling profiling uncovers cbl ubiquitin ligases as key immunotherapy targets. EMBO Molecular Medicine, 16:1791-1816, Jul 2024. URL: https://doi.org/10.1038/s44321-024-00098-y, doi:10.1038/s44321-024-00098-y. This article has 18 citations and is from a highest quality peer-reviewed journal.

  14. (NCT05107674 chunk 1): A Study of NX-1607 in Adults With Advanced Malignancies. Nurix Therapeutics, Inc.. 2021. ClinicalTrials.gov Identifier: NCT05107674

  15. (tench2026targetingcblubiquitin pages 1-5): Andrea J. Tench, Claire E. Martin, Craig D. Simpson, Leanne E. Wybenga-Groot, Diane Ly, Christopher Fladd, Melissa H. Elgie, Syed F. Ahmed, Roger Belizaire, Danny T. Huang, Anne-Claude Gingras, and C. Jane McGlade. Targeting cbl ubiquitin ligase activation to downregulate tyrosine kinase signalling. bioRxiv, Mar 2026. URL: https://doi.org/10.64898/2026.03.16.712190, doi:10.64898/2026.03.16.712190. This article has 0 citations.

  16. (tench2026targetingcblubiquitin pages 16-19): Andrea J. Tench, Claire E. Martin, Craig D. Simpson, Leanne E. Wybenga-Groot, Diane Ly, Christopher Fladd, Melissa H. Elgie, Syed F. Ahmed, Roger Belizaire, Danny T. Huang, Anne-Claude Gingras, and C. Jane McGlade. Targeting cbl ubiquitin ligase activation to downregulate tyrosine kinase signalling. bioRxiv, Mar 2026. URL: https://doi.org/10.64898/2026.03.16.712190, doi:10.64898/2026.03.16.712190. This article has 0 citations.

  17. (chocarro2024pd1lag3cosignalingprofiling pages 10-10): Luisa Chocarro, Ester Blanco, Leticia Fernandez-Rubio, Maider Garnica, Miren Zuazo, Maria Jesus Garcia, Ana Bocanegra, Miriam Echaide, Colette Johnston, Carolyn J Edwards, James Legg, Andrew J Pierce, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Ruth Vera, Karina Ausin, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Grazyna Kochan, and David Escors. Pd-1/lag-3 co-signaling profiling uncovers cbl ubiquitin ligases as key immunotherapy targets. EMBO Molecular Medicine, 16:1791-1816, Jul 2024. URL: https://doi.org/10.1038/s44321-024-00098-y, doi:10.1038/s44321-024-00098-y. This article has 18 citations and is from a highest quality peer-reviewed journal.

Citations

  1. nath2024mechanismsofcblmediated pages 1-3
  2. duan2003cblmediatedubiquitinylationis pages 1-1
  3. pinillamacua2023cblandcblb pages 1-2
  4. liyasova2015molecularpathwayscbl pages 1-2
  5. yang2024blnknegativelyregulates pages 6-7
  6. zutshi2024cblandcblb pages 15-16
  7. yang2024blnknegativelyregulates pages 7-8
  8. tench2026targetingcblubiquitin pages 1-5
  9. ren2024theroleof pages 1-2
  10. zutshi2024cblandcblb pages 1-2
  11. yang2024blnknegativelyregulates pages 1-2
  12. tench2026targetingcblubiquitin pages 16-19
  13. https://clinicaltrials.gov/study/NCT05107674
  14. https://clinicaltrials.gov/study/NCT05662397
  15. https://doi.org/10.1091/mbc.e23-02-0058
  16. https://doi.org/10.1016/j.isci.2024.109912
  17. https://doi.org/10.1073/pnas.2400920121
  18. https://doi.org/10.3390/life14121592
  19. https://doi.org/10.3389/fphar.2024.1432545
  20. https://doi.org/10.1038/s44321-024-00098-y
  21. https://doi.org/10.1016/j.isci.2024.109912,
  22. https://doi.org/10.3390/life14121592,
  23. https://doi.org/10.3389/fphar.2024.1432545,
  24. https://doi.org/10.1074/jbc.m304474200,
  25. https://doi.org/10.1091/mbc.e23-02-0058,
  26. https://doi.org/10.1158/1078-0432.ccr-13-2490,
  27. https://doi.org/10.1073/pnas.2400920121,
  28. https://doi.org/10.1038/s44321-024-00098-y,
  29. https://doi.org/10.64898/2026.03.16.712190,

📄 View Raw YAML

 
id: P22682
gene_symbol: Cbl
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Cbl is a RING-type E3 ubiquitin-protein ligase and phosphotyrosine-binding adaptor that recognizes activated receptor tyrosine kinases and other signaling proteins. It ubiquitinates receptors and signaling components to promote endocytosis, lysosomal or proteasomal turnover, and negative feedback on EGFR, PDGFRA, KIT, CSF1R, SRC-family, and immune-receptor signaling pathways.
existing_annotations:
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
    action: ACCEPT
    reason: Site where Cbl engages activated membrane receptors; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Very broad BP (IBA) consistent with Cbl as a signaling protein; correct but unspecific, retained as non-core context.
    action: KEEP_AS_NON_CORE
    reason: High-level signaling context; correct but non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).'
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cbl colocalizes with FGFR2 in lipid rafts at the cell membrane (UniProt Note); a microdomain refinement of its membrane recruitment (IBA).
    action: KEEP_AS_NON_CORE
    reason: Lipid-raft microdomain localization; refinement of membrane recruitment, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0030971
    label: receptor tyrosine kinase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cbl binds activated RTKs (KIT, FLT1, PDGFRA/B, CSF1R, EPHA8, KDR, EGFR) via its TKB domain as the substrate-selection step of receptor downregulation (IBA).
    action: ACCEPT
    reason: Core recognition of RTK substrates; central to Cbl's negative-regulator role.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.'
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'Core substrate-recognition MF: the TKB/PTB (SH2-like) domain binds phosphotyrosine on activated receptors, the mechanism by which Cbl selects substrates.'
    action: ACCEPT
    reason: Defines how Cbl recognizes activated, phosphorylated receptor substrates; core adaptor MF.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.'
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Core catalytic MF (EC 2.3.2.27) describing the ubiquitin transfer reaction Cbl catalyzes; equivalent framing of its RING E3 activity, retained as a core function.
    action: ACCEPT
    reason: Core catalytic activity matching the UniProt CATALYTIC ACTIVITY/EC 2.3.2.27 reaction.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Cbl has one functional Ca2+-binding EF-hand within the TKB domain (structural/regulatory), but Ca2+ binding is not a core function and is captured by the TKB domain architecture.
    action: MARK_AS_OVER_ANNOTATED
    reason: Single structural EF-hand Ca2+ site; not a core MF.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Consistent with UniProt SUBCELLULAR LOCATION (Cytoplasm); a correct, if general, parent localization for the cytosolic Cbl pool.
    action: ACCEPT
    reason: Matches UniProt cytoplasmic localization; general but correct core compartment.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
    action: KEEP_AS_NON_CORE
    reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
    action: ACCEPT
    reason: Site where Cbl engages activated membrane receptors; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Broad pathway term (IEA) situating Cbl within receptor signaling; correct but unspecific, retained as non-core context.
    action: KEEP_AS_NON_CORE
    reason: Broad correct context term; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).'
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Reflects the structural Zn(2+) coordinated by the RING-type zinc finger; structural, not an independent function, and subsumed by the E3 ligase activity annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Structural zinc of the RING domain; over-annotated as a standalone MF.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.'
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Bare 'transferase activity' is far too generic for an E3 ligase whose specific activity is ubiquitin transfer; replace with the specific ubiquitin-protein transferase term.
    action: MODIFY
    reason: Uninformatively general parent of the specific ubiquitin transferase activity.
    proposed_replacement_terms:
    - id: GO:0004842
      label: ubiquitin-protein transferase activity
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0023051
    label: regulation of signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Top-level vague term; Cbl predominantly negatively regulates signaling by receptor downregulation, so refine to negative regulation of signal transduction.
    action: MODIFY
    reason: Very general; replace with the negative-regulation child reflecting Cbl's role.
    proposed_replacement_terms:
    - id: GO:0009968
      label: negative regulation of signal transduction
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).'
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Generic parent of the structural zinc/calcium binding; uninformative and not a function in its own right.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic metal-binding term with no independent functional meaning.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**RING finger**: binds E2 enzymes and is required for ubiquitin transfer to substrates.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:1902531
    label: regulation of intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Overly broad; Cbl's documented role is negative regulation via receptor ubiquitination/downregulation, better captured by negative regulation of signal transduction.
    action: MODIFY
    reason: Too general; a more specific negative-regulation child is available.
    proposed_replacement_terms:
    - id: GO:0009968
      label: negative regulation of signal transduction
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A central negative-feedback regulator of receptor signaling** by linking receptor activation to ubiquitin-dependent receptor trafficking and degradation (EGFR archetype).'
- term:
    id: GO:2000583
    label: regulation of platelet-derived growth factor receptor-alpha signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cbl (with Cbl-b) provides feedback inhibition of ciliary PDGFRA signaling via PDGFRA ubiquitination and internalization (IMP:UniProtKB; PubMed:29237719).
    action: ACCEPT
    reason: Specific, experimentally supported PDGFRA negative-feedback role; mirrors UniProt FUNCTION.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-family ubiquitination of activated RTKs (EGFR paradigm) is a central, experimentally grounded function that links phosphorylation-dependent recognition to endosomal sorting and receptor downregulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12559036
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23374343
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23799367
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24440350
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27474268
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7657591
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9890970
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl multi/poly-ubiquitinates activated RTKs (e.g. CSF1R multiubiquitination), a documented degradative outcome of its ligase activity.
    action: ACCEPT
    reason: Specific, correct ubiquitin-chain type produced by Cbl on receptor substrates.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Focal-adhesion localization (IEA/ISO) fits Cbl's roles in adhesion/cytoskeletal signaling; a context-specific site rather than a core compartment.
    action: KEEP_AS_NON_CORE
    reason: Context-specific adhesion-site localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).'
    action: ACCEPT
    reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl also monoubiquitinates receptors, a recognized signal for endocytic sorting; a valid specific ubiquitination outcome of Cbl.
    action: ACCEPT
    reason: Documented mono-ubiquitination activity supporting receptor internalization.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Single IEA annotation with no established Cbl-specific mechanism; weak but not contradicted, so retained as non-core rather than removed.
    action: KEEP_AS_NON_CORE
    reason: Weak electronic annotation; retain as non-core, mechanism unclear.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.'
- term:
    id: GO:0008584
    label: male gonad development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Developmental annotation (IEA) reflecting pleiotropic roles in organ development; not a core molecular mechanism.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental role; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In intestine, c-Cbl and Cbl-b are partly redundant
- term:
    id: GO:0010332
    label: response to gamma radiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA stimulus-response term tied to DNA-damage context; peripheral and without specific Cbl mechanism.
    action: KEEP_AS_NON_CORE
    reason: Generic radiation-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Broad stimulus-response term (IEA) lacking a specific Cbl mechanism; peripheral contextual annotation.
    action: KEEP_AS_NON_CORE
    reason: Vague stimulus-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
    action: ACCEPT
    reason: Direct experimental annotation of Cbl's core ubiquitination process.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Redundant generic kinase-binding term superseded by the more specific protein/receptor tyrosine kinase binding annotations that describe Cbl's actual substrate recognition.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic and redundant with the specific tyrosine-kinase-binding MFs.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Axonal localization (IEA/ISO) is a neuronal-context site consistent with Eph-receptor regulation; not a core compartment for the E3/adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-context localization; specialized, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Growth-cone localization (IEA/ISO) reflects neuronal/cytoskeletal context (e.g. Eph signaling); peripheral specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal context localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA hormone-response term, likely tied to gonad context; peripheral with no specific Cbl mechanism.
    action: KEEP_AS_NON_CORE
    reason: Generic hormone-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0036120
    label: cellular response to platelet-derived growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl acts in PDGF receptor signaling responses (IEA); the mechanistic core (PDGFRA regulation) is captured separately, so this broad response is non-core.
    action: KEEP_AS_NON_CORE
    reason: Broad PDGF-response context; mechanism captured by the PDGFRA-regulation term.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0036312
    label: phosphatidylinositol 3-kinase regulatory subunit binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Phospho-Cbl interacts with PIK3R1 to recruit PI3K (UniProt SUBUNIT); a genuine partner interaction supporting PI3K coupling but downstream of Cbl's core E3 role.
    action: KEEP_AS_NON_CORE
    reason: Documented PIK3R1 interaction; secondary/effector partner binding, not core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA nutrient-deprivation response with no Cbl-specific mechanism; peripheral contextual annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic starvation-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic survival-signaling outcome; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.'
- term:
    id: GO:0043303
    label: mast cell degranulation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl modulates mast-cell signaling (KIT/FcεRI) affecting degranulation (IEA); a downstream cell-type-specific physiological readout.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific physiological outcome; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Single IEA stimulus-response annotation with no Cbl-specific mechanism; peripheral.
    action: KEEP_AS_NON_CORE
    reason: Generic chemical-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
    action: KEEP_AS_NON_CORE
    reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Receptor tyrosine kinases (RTKs)
- term:
    id: GO:0048260
    label: positive regulation of receptor-mediated endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
    action: ACCEPT
    reason: Cbl actively drives receptor internalization — core downregulation mechanism.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Perinuclear localization (IEA/ISO) is consistent with endosomal/recycling trafficking compartments; a sub-cytoplasmic refinement, non-core.
    action: KEEP_AS_NON_CORE
    reason: Sub-cytoplasmic trafficking-compartment localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Runs counter to Cbl's degradative role; likely over-annotation.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0050860
    label: negative regulation of T cell receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
    action: KEEP_AS_NON_CORE
    reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl undergoes autoubiquitination (it is itself ubiquitinated leading to proteasomal turnover, per UniProt PTM), a genuine regulatory activity of the RING ligase.
    action: ACCEPT
    reason: Self-ubiquitination is a documented PTM/activity consistent with RING E3 function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Phospho-Cbl recruits PI3K (e.g. Tyr-731 form in osteoclasts) promoting PI3K/AKT signaling; a context-specific positive role distinct from its main negative-regulator function.
    action: KEEP_AS_NON_CORE
    reason: Context-specific PI3K/AKT-promoting role; downstream, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
    action: MODIFY
    reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
    proposed_replacement_terms: &id001
    - id: GO:0016567
      label: protein ubiquitination
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Hypoxia-response annotation (IEA) is a contextual stimulus-response with no specific Cbl mechanism asserted; peripheral.
    action: KEEP_AS_NON_CORE
    reason: Generic stimulus-response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:1990090
    label: cellular response to nerve growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Reflects Cbl participation downstream of NGF/TrkA receptor signaling (IEA); a context response rather than a core mechanism.
    action: KEEP_AS_NON_CORE
    reason: Downstream growth-factor response context; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Across receptor systems, c-Cbl is best understood as an **activation-dependent negative regulator** of signaling
- term:
    id: GO:1990782
    label: protein tyrosine kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cbl binds activated tyrosine kinases (RTKs and SRC-family) through its TKB domain to target them for ubiquitination; a core, mechanistically central interaction MF.
    action: ACCEPT
    reason: Core adaptor MF — recognition of the tyrosine-kinase substrates Cbl downregulates.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
    action: KEEP_AS_NON_CORE
    reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
    action: ACCEPT
    reason: Site where Cbl engages activated membrane receptors; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005929
    label: cilium
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: 'Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).'
    action: ACCEPT
    reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
    action: ACCEPT
    reason: Direct experimental annotation of Cbl's core ubiquitination process.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic survival-signaling outcome; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.'
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
    action: KEEP_AS_NON_CORE
    reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Receptor tyrosine kinases (RTKs)
- term:
    id: GO:0048260
    label: positive regulation of receptor-mediated endocytosis
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
    action: ACCEPT
    reason: Cbl actively drives receptor internalization — core downregulation mechanism.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Runs counter to Cbl's degradative role; likely over-annotation.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0050860
    label: negative regulation of T cell receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
    action: KEEP_AS_NON_CORE
    reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Phospho-Cbl recruits PI3K (e.g. Tyr-731 form in osteoclasts) promoting PI3K/AKT signaling; a context-specific positive role distinct from its main negative-regulator function.
    action: KEEP_AS_NON_CORE
    reason: Context-specific PI3K/AKT-promoting role; downstream, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
    action: MODIFY
    reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
    proposed_replacement_terms: *id001
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0097229
    label: sperm end piece
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Sperm end-piece localization (ISO only) is a highly tissue-specific finding unrelated to Cbl's core signaling-attenuation role.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific ISO localization; peripheral, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cbl multi/poly-ubiquitinates activated RTKs (e.g. CSF1R multiubiquitination), a documented degradative outcome of its ligase activity.
    action: ACCEPT
    reason: Specific, correct ubiquitin-chain type produced by Cbl on receptor substrates.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Focal-adhesion localization (IEA/ISO) fits Cbl's roles in adhesion/cytoskeletal signaling; a context-specific site rather than a core compartment.
    action: KEEP_AS_NON_CORE
    reason: Context-specific adhesion-site localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cbl also monoubiquitinates receptors, a recognized signal for endocytic sorting; a valid specific ubiquitination outcome of Cbl.
    action: ACCEPT
    reason: Documented mono-ubiquitination activity supporting receptor internalization.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Redundant generic kinase-binding term superseded by the more specific protein/receptor tyrosine kinase binding annotations that describe Cbl's actual substrate recognition.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic and redundant with the specific tyrosine-kinase-binding MFs.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Axonal localization (IEA/ISO) is a neuronal-context site consistent with Eph-receptor regulation; not a core compartment for the E3/adaptor function.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-context localization; specialized, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Growth-cone localization (IEA/ISO) reflects neuronal/cytoskeletal context (e.g. Eph signaling); peripheral specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal context localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0036312
    label: phosphatidylinositol 3-kinase regulatory subunit binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Phospho-Cbl interacts with PIK3R1 to recruit PI3K (UniProt SUBUNIT); a genuine partner interaction supporting PI3K coupling but downstream of Cbl's core E3 role.
    action: KEEP_AS_NON_CORE
    reason: Documented PIK3R1 interaction; secondary/effector partner binding, not core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Mechanistically, BLNK modulated c-Cbl phosphorylation and **PI3K-associated actin remodeling**, linking c-Cbl to cytoskeletal outputs required for renal macrophage recruitment.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cbl influences survival signaling (e.g. via PI3K/AKT) in some contexts (IEA/ISO); a pleiotropic downstream outcome, not a core mechanism.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic survival-signaling outcome; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.'
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Perinuclear localization (IEA/ISO) is consistent with endosomal/recycling trafficking compartments; a sub-cytoplasmic refinement, non-core.
    action: KEEP_AS_NON_CORE
    reason: Sub-cytoplasmic trafficking-compartment localization; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cbl undergoes autoubiquitination (it is itself ubiquitinated leading to proteasomal turnover, per UniProt PTM), a genuine regulatory activity of the RING ligase.
    action: ACCEPT
    reason: Self-ubiquitination is a documented PTM/activity consistent with RING E3 function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:1990782
    label: protein tyrosine kinase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cbl binds activated tyrosine kinases (RTKs and SRC-family) through its TKB domain to target them for ubiquitination; a core, mechanistically central interaction MF.
    action: ACCEPT
    reason: Core adaptor MF — recognition of the tyrosine-kinase substrates Cbl downregulates.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**TKBD/TKB**: a composite domain comprising a **4-helix bundle**, **EF-hand**, and an **SH2-like phosphotyrosine-recognition module** that mediates binding to phosphorylated targets.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9763892
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl's core action is to destabilize/degrade its substrates; a 'protein stabilization' annotation (IEA/ISO/ISS) is at odds with its principal degradative function and likely over-propagated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Runs counter to Cbl's degradative role; likely over-annotation.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0050860
    label: negative regulation of T cell receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl negatively regulates TCR signaling by ubiquitinating/downregulating proximal components (ZAP70, LAT, Src-family kinases); cell-type-specific instance of receptor downregulation.
    action: KEEP_AS_NON_CORE
    reason: Immune-specific instance of Cbl's negative receptor regulation; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl dampens TCR signaling (with SLA2/ZAP70) and thereby T-cell activation; an important but downstream, cell-type-specific consequence of its E3/adaptor role.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic immune-regulatory outcome; downstream of core E3 function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: A 2024 immune-focused review summarizes that Cbl-family E3 ligases ubiquitinate and downregulate proximal signaling components including **TCR/CD3 subunits**, Src-family kinases **Fyn** and **Lck**, the adaptor **LAT**, and other pathway components in T and NK cells.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: K63-linked chains drive endocytic/trafficking fates not proteasomal degradation; supported only by IEA/ISO/ISS, so generalize to the well-supported parent protein ubiquitination rather than asserting a specific chain linkage for mouse Cbl.
    action: MODIFY
    reason: Chain-linkage specificity is only electronically inferred; generalize to supported parent.
    proposed_replacement_terms: *id001
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:12754251
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:15962011
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15383614
  review:
    summary: Cbl is recruited to activated receptors at the plasma membrane where it ubiquitinates them (IDA:MGI); a core functional location.
    action: ACCEPT
    reason: Site where Cbl engages activated membrane receptors; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISO
  original_reference_id: PMID:11823423
  review:
    summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
    action: ACCEPT
    reason: Direct experimental annotation of Cbl's core ubiquitination process.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:11823423
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IGI
  original_reference_id: PMID:11823423
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:12754251
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0070086
    label: ubiquitin-dependent endocytosis
  evidence_type: ISO
  original_reference_id: PMID:11823423
  review:
    summary: 'Core BP: Cbl ubiquitination of activated receptors couples them to the endocytic machinery for internalization (IMP:MGI), the adaptor/trafficking arm of its function.'
    action: ACCEPT
    reason: Directly links Cbl ubiquitination to receptor endocytosis; core trafficking role.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23457600
  review:
    summary: 'Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).'
    action: ACCEPT
    reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:23457600
  review:
    summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
    action: ACCEPT
    reason: Direct experimental annotation of Cbl's core ubiquitination process.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:23457600
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23457600
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:15383614
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:23457600
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:23457600
  review:
    summary: 'Core catalytic MF: RING-type E3 ligase that recruits E2~ubiquitin via its RING finger and transfers ubiquitin to activated receptor substrates; strongly supported (IDA:MGI plus IBA/IMP/ISS/TAS).'
    action: ACCEPT
    reason: Best-supported core molecular function with direct experimental evidence.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0070086
    label: ubiquitin-dependent endocytosis
  evidence_type: IMP
  original_reference_id: PMID:15383614
  review:
    summary: 'Core BP: Cbl ubiquitination of activated receptors couples them to the endocytic machinery for internalization (IMP:MGI), the adaptor/trafficking arm of its function.'
    action: ACCEPT
    reason: Directly links Cbl ubiquitination to receptor endocytosis; core trafficking role.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0016600
    label: flotillin complex
  evidence_type: IDA
  original_reference_id: PMID:11001060
  review:
    summary: Association with the flotillin complex (IDA:BHF-UCL) reflects membrane-microdomain/endocytic context; a real but peripheral complex membership.
    action: KEEP_AS_NON_CORE
    reason: Specific microdomain complex membership; peripheral to core function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9447983
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9680646
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9680706
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9682158
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9682182
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9763891
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9763892
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9817994
  review:
    summary: Cbl is a baseline cytosolic adaptor/E3 (TAS:Reactome and ISO), recruited from the cytosol to activated membrane receptor complexes; a core site of action.
    action: ACCEPT
    reason: Primary baseline localization of the cytosolic adaptor/E3; well supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best viewed as a **cytosolic adaptor/E3** that is recruited to **activated plasma-membrane signaling complexes** and subsequently to **endocytic/endosomal trafficking sites**, where it ubiquitinates receptors and associated proteins to direct trafficking fate
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Core BP capturing Cbl's central activity of conjugating ubiquitin to substrate proteins (IDA:MGI); directly downstream of its E3 ligase MF.
    action: ACCEPT
    reason: Direct experimental annotation of Cbl's core ubiquitination process.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- term:
    id: GO:0032487
    label: regulation of Rap protein signal transduction
  evidence_type: IMP
  original_reference_id: PMID:12671687
  review:
    summary: Cbl modulates Rap GTPase signaling (IMP), plausibly via C3G/CrkL adaptor complexes; a specific but downstream signaling-regulation role.
    action: KEEP_AS_NON_CORE
    reason: Specific downstream small-GTPase signaling regulation; non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**A context-dependent signaling rheostat** in immune and myeloid cells, where adaptor networks (e.g., BLNK/Fyn/PI3K in CLR signaling) tune c-Cbl phosphorylation state and thereby cytoskeletal/migratory behavior and host defense.'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:29237719
  review:
    summary: Reported Golgi localization (IDA:UniProtKB; PubMed:29237719) in the ciliary PDGFRA context; a genuine secondary compartment, not Cbl's principal site of action.
    action: KEEP_AS_NON_CORE
    reason: Documented but secondary localization; keep as non-core (do not remove a sourced IDA).
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IDA
  original_reference_id: PMID:29237719
  review:
    summary: Cbl localizes to the primary cilium where it regulates ciliary PDGFRA signaling (IDA:UniProtKB; PubMed:29237719); a real but context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Genuine ciliary localization tied to PDGFRA feedback; specialized, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In macrophages it also associates with F-actin/podosome-related structures during migration signaling.
- term:
    id: GO:2000583
    label: regulation of platelet-derived growth factor receptor-alpha signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:29237719
  review:
    summary: Cbl (with Cbl-b) provides feedback inhibition of ciliary PDGFRA signaling via PDGFRA ubiquitination and internalization (IMP:UniProtKB; PubMed:29237719).
    action: ACCEPT
    reason: Specific, experimentally supported PDGFRA negative-feedback role; mirrors UniProt FUNCTION.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-family ubiquitination of activated RTKs (EGFR paradigm) is a central, experimentally grounded function that links phosphorylation-dependent recognition to endosomal sorting and receptor downregulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8551236
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21830225
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Core BP: Cbl-mediated ubiquitination routes substrate receptors to proteasomal/lysosomal degradation, terminating signaling (IMP:MGI).'
    action: ACCEPT
    reason: Core outcome of Cbl ubiquitination — substrate degradation; experimentally supported.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation
- term:
    id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Archetypal core role: Cbl ubiquitinates activated EGFR to drive its endosomal/lysosomal sorting and signal termination (IDA:MGI plus IBA/IMP/IGI/ISS).'
    action: ACCEPT
    reason: Canonical, experimentally grounded negative-feedback role on EGFR signaling.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**EGFR** is a canonical substrate/target: Cbl-mediated ubiquitination is required for efficient **lysosomal sorting/degradation** of EGFR after ligand stimulation; direct binding can occur via EGFR **pY1045** to the Cbl TKB domain, with an alternative Grb2-mediated route.'
- term:
    id: GO:0048260
    label: positive regulation of receptor-mediated endocytosis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl promotes ligand-induced internalization of its RTK substrates (e.g. CSF1R multiubiquitination and endocytosis); a core adaptor/trafficking function (ISS).
    action: ACCEPT
    reason: Cbl actively drives receptor internalization — core downregulation mechanism.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: c-Cbl is best understood as an **activation-dependent negative regulator** of signaling that couples recognition of **phosphotyrosine-containing activated signaling complexes** to **ubiquitin-dependent downregulation** (often routing to lysosomes for receptor degradation) and/or **proteasomal degradation** of signaling proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11152963
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16455755
  review:
    summary: Bare 'protein binding' (12x IPI) is uninformative; Cbl's meaningful interactions are captured by specific phosphotyrosine/kinase-binding terms and named-partner annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding conveys no functional information; always over-annotated.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
- term:
    id: GO:0046875
    label: ephrin receptor binding
  evidence_type: IPI
  original_reference_id: PMID:18034775
  review:
    summary: Cbl binds Eph receptors (EPHB1, EPHA8) to drive their ubiquitination/degradation (IPI); a real but substrate-specific interaction, an instance of its general RTK-binding role.
    action: KEEP_AS_NON_CORE
    reason: Real specific RTK interaction; non-core instance of the general substrate-binding function.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Receptor tyrosine kinases (RTKs)
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl is a ubiquitin ligase, not a protein kinase; it is phosphorylated BY kinases but does not catalyze protein phosphorylation. This ISS annotation reverses the direction of the modification and is incorrect.
    action: REMOVE
    reason: Cbl has no kinase activity; annotation contradicts its biochemistry (it is a substrate, not a kinase).
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: Cbl-family proteins are **RING-type E3 ligases**, meaning they **do not form a catalytic ubiquitin thioester intermediate**; instead, they bring an **E2~ubiquitin conjugate** into proximity with the substrate to enable transfer.
- term:
    id: GO:0045453
    label: bone resorption
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cbl is required for osteoclastic bone resorption (ISS; UniProt FUNCTION); an important tissue-level physiological role downstream of its signaling functions.
    action: KEEP_AS_NON_CORE
    reason: Tissue-level osteoclast physiology; downstream, non-core.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: In intestine, c-Cbl and Cbl-b are partly redundant
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: IPI
  original_reference_id: PMID:9447983
  review:
    summary: Reflects proline-rich-mediated recruitment of SH3-containing adaptors (Grb2, CD2AP/CIN85) but is a generic binding descriptor that does not convey Cbl's catalytic/adaptor role.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic binding MF; partner-specific adaptor links are captured elsewhere.
    supported_by:
    - reference_id: UniProt:P22682
      supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
    - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
      supporting_text: '**Indirect recruitment through adaptors** (e.g., Grb2 linking EGFR to Cbl via Grb2 SH2–pEGFR and Grb2 SH3–Cbl proline-rich interactions).'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11001060
  title: CAP defines a second signalling pathway required for insulin-stimulated glucose transport.
  findings: []
- id: PMID:11152963
  title: SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins.
  findings: []
- id: PMID:11823423
  title: A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling.
  findings: []
- id: PMID:12559036
  title: CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl.
  findings: []
- id: PMID:12671687
  title: Negative regulation of Rap1 activation by the Cbl E3 ubiquitin ligase.
  findings: []
- id: PMID:12754251
  title: Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis.
  findings: []
- id: PMID:15383614
  title: c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15.
  findings: []
- id: PMID:15962011
  title: Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation.
  findings: []
- id: PMID:16455755
  title: Spatial and temporal regulation of GLUT4 translocation by flotillin-1 and caveolin-3 in skeletal muscle cells.
  findings: []
- id: PMID:18034775
  title: Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway.
  findings: []
- id: PMID:21830225
  title: SH3KBP1-binding protein 1 prevents epidermal growth factor receptor degradation by the interruption of c-Cbl-CIN85 complex.
  findings: []
- id: PMID:23374343
  title: Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation.
  findings: []
- id: PMID:23457600
  title: Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells.
  findings: []
- id: PMID:23799367
  title: Threshold-controlled ubiquitination of the EGFR directs receptor fate.
  findings: []
- id: PMID:24440350
  title: Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.
  findings: []
- id: PMID:27474268
  title: Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation.
  findings: []
- id: PMID:29237719
  title: IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases.
  findings: []
- id: PMID:7657591
  title: Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.
  findings: []
- id: PMID:8551236
  title: Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.
  findings: []
- id: PMID:9447983
  title: A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes.
  findings: []
- id: PMID:9890970
  title: Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase.
  findings: []
- id: Reactome:R-MMU-9680646
  title: Pik3r11:Pik3ca,b,d (Pi3k), Plcg2 (PLCgamma2), Grb2:Sos1, Shc1 (Shc), Ptpn11 (Shp2), Grb2:Gab2, Grb2:Gab3, Grap2 (MONA), Cbl:Grb2, Inpp5d (SHIP1), Inppl1 (SHIP2)  bind p-8Y-Csf1r and are activated
  findings: []
- id: Reactome:R-MMU-9680706
  title: Csf1r trans-autophosphorylates on multiple tyrosine residues
  findings: []
- id: Reactome:R-MMU-9682158
  title: Csf1r-associated Plcg2 hydrolyzes phosphatidylcholine yielding choline phosphate and 1,2-diacylglycerol
  findings: []
- id: Reactome:R-MMU-9682182
  title: Csf1r-associated PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate
  findings: []
- id: Reactome:R-MMU-9763891
  title: Src family kinases phosphorylate Cbl in Csf1 dimer:p-Y559-Csf1r dimer:Cbl
  findings: []
- id: Reactome:R-MMU-9763892
  title: p-Y-Cbl autoubiquitinates and multiubiquitinates p-Y-559-Csf12
  findings: []
- id: Reactome:R-MMU-9817994
  title: Csf1 dimer:p-Y559-Csf1r dimer:Fyn,Hck,Src,Yes1 binds Cbl
  findings: []
- id: UniProt:P22682
  title: UniProt record for Cbl (P22682)
  findings: []
- id: file:mouse/Cbl/Cbl-deep-research-falcon.md
  title: Deep research report on Cbl (falcon)
  findings: []
core_functions:
- molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  description: Transfers ubiquitin to activated receptor tyrosine kinases and signaling substrates to attenuate signaling and promote receptor downregulation.
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0016567
    label: protein ubiquitination
  - id: GO:0042059
    label: negative regulation of epidermal growth factor receptor signaling pathway
  supported_by:
  - reference_id: UniProt:P22682
    supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
  - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
    supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
- molecular_function:
    id: GO:0030971
    label: receptor tyrosine kinase binding
  description: The TKB/phosphotyrosine-binding region recognizes activated receptor tyrosine kinases, positioning the RING E3 ligase domain for substrate ubiquitination.
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005886
    label: plasma membrane
  directly_involved_in:
  - id: GO:0070086
    label: ubiquitin-dependent endocytosis
  supported_by:
  - reference_id: UniProt:P22682
    supporting_text: 'FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors. Recognizes activated receptor tyrosine kinases and mediates their ubiquitination to terminate signaling. CATALYTIC ACTIVITY: transfers ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein lysine. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme; the N-terminus includes a phosphotyrosine binding/TKB domain.'
  - reference_id: file:mouse/Cbl/Cbl-deep-research-falcon.md
    supporting_text: c-Cbl catalyzes **transfer of ubiquitin from an E2~ubiquitin conjugate to lysine residues on substrate proteins** (E3 ubiquitin ligase activity), leading to mono- or polyubiquitination with downstream consequences (endocytosis/endosomal sorting, lysosomal degradation, proteasomal degradation, or signaling rewiring depending on context).
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []