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.
| 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. Proposed replacements: ubiquitin-protein 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. Proposed replacements: negative regulation of signal transduction 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. Proposed replacements: negative regulation of signal transduction 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 β 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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/FcΞ΅RI) 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 β 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 β 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 β 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 SH2βpEGFR and Grb2 SH3βCbl 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 β 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 β 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 β 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 SH2βpEGFR and Grb2 SH3βCbl 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 PDGFRΞ± 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 PDGFRΞ± 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 PDGFRΞ± 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 β 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 β 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl 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 SH2βpEGFR and Grb2 SH3βCbl proline-rich interactions). |
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