SOCS3 (Suppressor of cytokine signaling 3; also CIS-3, SSI-3) is a 225-residue cytoplasmic adaptor protein and a cytokine-inducible negative-feedback inhibitor of JAK-STAT signaling. It has a modular architecture comprising an N-terminal kinase inhibitory region (KIR, ~residues 22-33), an extended SH2 subdomain (ESS), a central SH2 domain (~residues 46-142), and a C-terminal SOCS box (~residues 177-224). Through its SH2 domain SOCS3 docks onto specific phosphotyrosine motifs on activated cytokine receptors, most notably gp130/IL6ST, but also LIFR, EPOR, the leptin receptor (LEPR), IL12RB2, CSF3R/G-CSF receptor and the insulin/IGF-I receptors, and onto activated JAK2. The KIR then acts as a pseudosubstrate that occupies the JAK catalytic groove and inhibits JAK kinase activity, blocking downstream STAT (especially STAT3) phosphorylation. Through its SOCS box SOCS3 recruits the Elongin B/C-Cullin5-RBX2 (ECS) module, functioning as the substrate-recognition subunit of a Cullin5-RING E3 ubiquitin ligase that targets bound receptor/JAK components for ubiquitination and proteasomal degradation. SOCS3 is transcriptionally induced by STAT3 (and other cytokine signals), establishing a classical negative-feedback loop. It is a principal physiological brake on IL-6 and leptin signaling and modulates erythropoiesis, immune and inflammatory responses (including Th17 biology), and metabolic signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0046426
negative regulation of receptor signaling pathway via JAK-STAT
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic (IBA) annotation to the defining SOCS3 process - negative feedback inhibition of JAK-STAT signaling. This is the central, well-supported biological role of SOCS3 and matches experimental (IMP) and ISS evidence.
Reason: Core function of SOCS3; concordant with experimental and orthology evidence across the SOCS family.
|
|
GO:0005126
cytokine receptor binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOCS3 SH2 domain docks onto phosphotyrosine motifs of activated cytokine receptors (gp130/IL6ST, LIFR, EPOR, LEPR, IL12RB2, CSF3R). Cytokine receptor binding captures this receptor-docking molecular function.
Reason: Well-supported SH2-mediated receptor docking; a core molecular activity enabling SOCS3 to act at receptor complexes.
|
|
GO:0019221
cytokine-mediated signaling pathway
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: SOCS3 acts within cytokine-mediated signaling pathways as a feedback inhibitor. The term is correct but high-level; the negative-regulation term (GO:0046426) is the more informative process annotation.
Reason: Correct but general process context; the specific negative-regulation-of-JAK-STAT term better represents the core role.
|
|
GO:0035556
intracellular signal transduction
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: Generic InterPro-derived process annotation. SOCS3 indeed participates in intracellular signal transduction, but this is non-specific relative to its JAK-STAT negative-regulation role.
Reason: Correct but uninformative high-level process; superseded by more specific JAK-STAT terms.
|
|
GO:0005515
protein binding
|
IPI
PMID:19027008 The role of microtubule-associated protein 1S in SOCS3 regul... |
KEEP AS NON CORE |
Summary: IntAct binding annotation for the SOCS3-MAP1S interaction. 'Protein binding' is uninformative as a molecular function; the specific partner (MAP1S) is captured in the reference findings.
Reason: Per curation guidelines, generic GO:0005515 'protein binding' is not a core informative MF; valid interaction evidence but kept non-core.
|
|
GO:0005515
protein binding
|
IPI
PMID:24728074 Enhanced prediction of Src homology 2 (SH2) domain binding p... |
KEEP AS NON CORE |
Summary: SH2-domain interactome screen reporting SOCS3 binding to phosphopeptides (e.g., KIT, MET). Generic 'protein binding' molecular function.
Reason: Generic protein-binding from a high-throughput SH2 screen; not a core informative MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:25203322 PKD1 phosphorylation-dependent degradation of SNAIL by SCF-F... |
KEEP AS NON CORE |
Summary: SOCS3-SNAI1 interaction reported in an EMT study focused on FBXO11/SNAIL. Generic 'protein binding' annotation.
Reason: Generic protein-binding; not a core informative MF for SOCS3.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
KEEP AS NON CORE |
Summary: Interactions from a proteome-scale binary interactome map (e.g., YES1, KIAA1958). Generic 'protein binding'.
Reason: High-throughput Y2H protein-binding; not a core informative MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
KEEP AS NON CORE |
Summary: Interactions from the reference human binary interactome map (e.g., YES1, TXK, BLK). Generic 'protein binding'.
Reason: High-throughput Y2H protein-binding; not a core informative MF.
|
|
GO:0001784
phosphotyrosine residue binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOCS3 SH2 domain recognizes phosphotyrosine motifs on activated receptors and JAK2; phosphotyrosine residue binding is a precise, mechanistically grounded molecular function for the SH2 module.
Reason: Accurate and informative MF capturing SH2-mediated pTyr recognition; a core docking activity.
|
|
GO:0035198
miRNA binding
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Ortholog-transferred (Ensembl Compara, from mouse O35718) miRNA-binding annotation. SOCS3 is not an established RNA/miRNA-binding protein; rather it is itself a target of miRNAs (e.g., miR-221). This appears to be an erroneous electronic transfer.
Reason: No credible evidence SOCS3 binds miRNA; likely spurious ortholog transfer, possibly confusing SOCS3-as-miRNA-target with miRNA binding.
|
|
GO:0097398
cellular response to interleukin-17
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog-transferred process annotation. SOCS3 is plausibly involved in IL-17-related inflammatory responses, but the link is indirect and not central to its molecular function.
Reason: Plausible but indirect process from electronic transfer; not a core function.
|
|
GO:0016567
protein ubiquitination
|
IEA
GO_REF:0000041 |
ACCEPT |
Summary: SOCS3 is the substrate-recognition subunit of an Elongin BC-Cullin5-RBX2 (ECS) E3 ubiquitin ligase via its SOCS box, mediating ubiquitination of bound receptor/JAK components. Protein ubiquitination is a correct and core process.
Reason: Core SOCS-box-mediated function; concordant with mechanistic literature (Kamura et al. 2004) and Reactome CSF3R/CRL5 ubiquitination events.
|
|
GO:0007259
cell surface receptor signaling pathway via JAK-STAT
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ISS (from mouse ortholog) placing SOCS3 in JAK-STAT signaling. SOCS3's role is specifically negative regulation of this pathway; the parent 'involved_in JAK-STAT' is correct but less informative than GO:0046426.
Reason: Correct pathway context but the negative-regulation term is the core, more informative annotation.
|
|
GO:0019210
kinase inhibitor activity
|
ISS
GO_REF:0000024 |
MODIFY |
Summary: SOCS3 inhibits JAK tyrosine kinase activity via its KIR (pseudosubstrate) and SH2 domain. Kinase inhibitor activity is correct; the more specific child term protein kinase inhibitor activity (GO:0004860) is preferred and is independently annotated (IDA/TAS).
Reason: Generalize to the more specific, experimentally supported protein kinase inhibitor activity.
Proposed replacements:
protein kinase inhibitor activity
|
|
GO:0007259
cell surface receptor signaling pathway via JAK-STAT
|
ISS
PMID:12754505 SOCS3 negatively regulates IL-6 signaling in vivo. |
KEEP AS NON CORE |
Summary: ISS from mouse Socs3, supported by in vivo evidence that Socs3 loss prolongs IL-6-induced STAT activation. Correct pathway context but less informative than the negative-regulation term.
Reason: Correct but general; negative-regulation-of-JAK-STAT is the core annotation.
|
|
GO:0019210
kinase inhibitor activity
|
ISS
PMID:12754505 SOCS3 negatively regulates IL-6 signaling in vivo. |
MODIFY |
Summary: Kinase-inhibitor MF transferred by similarity. As above, the specific protein kinase inhibitor activity term is preferred and is experimentally supported.
Reason: Generalize/refine to the more specific protein kinase inhibitor activity term.
Proposed replacements:
protein kinase inhibitor activity
|
|
GO:0070102
interleukin-6-mediated signaling pathway
|
ISS
PMID:12754505 SOCS3 negatively regulates IL-6 signaling in vivo. |
ACCEPT |
Summary: SOCS3 is the dominant feedback inhibitor of IL-6/gp130 signaling in vivo (Croker et al. 2003); involvement in the IL-6-mediated signaling pathway is well-supported and biologically central.
Reason: Strongly supported, specific, and central to SOCS3 biology (IL-6 brake).
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6785860 |
KEEP AS NON CORE |
Summary: SOCS3 acts in the cytosol and at the cytoplasmic face of receptor complexes. Cytosolic localization is correct but is a general location, not a core function.
Reason: Correct subcellular location; one of many redundant Reactome cytosol annotations.
|
|
GO:0072540
T-helper 17 cell lineage commitment
|
TAS
PMID:27893700 Trans-presentation of IL-6 by dendritic cells is required fo... |
KEEP AS NON CORE |
Summary: SOCS3 modulates the IL-6/STAT3 axis that drives Th17 differentiation; this is a downstream physiological/developmental consequence rather than SOCS3's molecular core function.
Reason: Valid process context (IL-6/Th17 axis) but a pleiotropic, downstream role, not core.
|
|
GO:0004860
protein kinase inhibitor activity
|
IDA
PMID:9727029 Interaction of human suppressor of cytokine signaling (SOCS)... |
ACCEPT |
Summary: Direct-assay annotation for SOCS3 protein kinase inhibitor activity. SOCS3 inhibits JAK tyrosine kinase via its KIR/SH2 modules. Although the cached abstract title names SOCS-2/IGF-IR, this is the curator-assigned experimental evidence for SOCS3 kinase-inhibitor activity and the function is correct for SOCS3.
Reason: Core molecular function of SOCS3 (KIR-mediated JAK inhibition); per guidelines an experimental annotation is not removed on the basis of an abstract-only paralog title.
|
|
GO:0009898
cytoplasmic side of plasma membrane
|
IDA
PMID:9727029 Interaction of human suppressor of cytokine signaling (SOCS)... |
KEEP AS NON CORE |
Summary: SOCS3 is recruited to phosphorylated receptor cytoplasmic tails at the inner face of the plasma membrane, consistent with this location. Accurate but a location, not a core molecular function.
Reason: Correct site of action (receptor tails at the membrane); supporting location rather than core function.
|
|
GO:0046426
negative regulation of receptor signaling pathway via JAK-STAT
|
IMP
PMID:25019494 MiR-221 accentuates IFNΧ³s anti-HCV effect by downregulating ... |
ACCEPT |
Summary: Experimental (IMP) support that modulating SOCS3 levels (via miR-221) alters JAK-STAT signaling output - downregulating SOCS3 relieves inhibition and enhances IFN/JAK/STAT signaling. Confirms SOCS3 as a negative regulator of JAK-STAT.
Reason: Core function; experimentally supported negative regulation of JAK-STAT signaling.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1112755 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (SOCS3 binds IL6ST). Correct location annotation.
Reason: Correct subcellular location; redundant with other cytosol annotations.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-6790041 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization annotation. Correct but redundant.
Reason: Correct location; one of many redundant Reactome cytosol annotations.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-877269 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (SOCS-1/SOCS-3 bind p-JAK2). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8848110 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (SOCS3 binds activated PTK6). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8848178 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (STAT3 stimulates SOCS3 expression). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8952039 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (CRL5/neddylation pathway). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8952044 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (CRL5/neddylation pathway). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8955241 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (CAND1/CRL regulation). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8955289 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (COMMD/CAND1/CRL regulation). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8956040 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (COP9 signalosome deneddylation). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9705738 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (SOCS1,3 ubiquitinates CSF3R within a CUL5/ELOB/ELOC/RNF7 complex). Correct location and consistent with SOCS3 E3-ligase function.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-NUL-1169195 |
KEEP AS NON CORE |
Summary: Reactome cytosol localization (SOCS binding to growth hormone receptor). Correct location.
Reason: Correct location; redundant Reactome cytosol annotation.
|
|
GO:0004860
protein kinase inhibitor activity
|
TAS
PMID:9266833 Cloning and functional analysis of new members of STAT induc... |
ACCEPT |
Summary: TAS annotation for SOCS3 (SSI-3) protein kinase inhibitor activity from the SSI-2/SSI-3 cloning/functional paper. Concordant with the IDA and ISS kinase-inhibitor annotations; reflects KIR-mediated JAK inhibition.
Reason: Core molecular function; corroborates the protein kinase inhibitor activity of SOCS3.
|
|
GO:0043066
negative regulation of apoptotic process
|
TAS
PMID:9266833 Cloning and functional analysis of new members of STAT induc... |
KEEP AS NON CORE |
Summary: Based on forced SSI-3/SOCS3 expression suppressing the apoptotic effect of LIF in M1 myeloid cells. This is an indirect, downstream consequence of blocking LIF/gp130/STAT3 signaling rather than a direct anti-apoptotic molecular activity, and is context-dependent (SOCS3 can be pro- or anti-apoptotic depending on cell type).
Reason: Indirect, context-dependent downstream effect of JAK-STAT inhibition; retained but not a core function.
|
Q: To what extent does SOCS3-mediated ubiquitination/proteasomal degradation of receptor complexes (via the Cul5 ECS ligase) contribute to signal termination versus the direct KIR-mediated kinase-inhibition mechanism, and are these separable in vivo?
Q: Which receptor phosphotyrosine motifs and JAK isoforms are the physiologically dominant SOCS3 targets in different tissues (liver, adipose, immune cells)?
Experiment: Separation-of-function mutants (KIR-dead vs SOCS-box-dead vs SH2-dead) expressed at endogenous levels, assayed for IL-6/gp130 STAT3 signaling kinetics and receptor/JAK ubiquitination, to dissect the relative contribution of kinase inhibition versus E3-ligase-mediated degradation.
Experiment: Quantitative proteomics (ubiquitinome/degradomics) in SOCS3-null versus reconstituted cells after IL-6/EPO/leptin stimulation to identify the physiological SOCS3 ECS-ligase substrates.
Journal of research for the SOCS3 gene review. Provenance recorded inline as
[PMID:xxxx "verbatim quote"] or [UniProt O14543] where appropriate.
GOA carries several GO:0005515 "protein binding" IPI annotations from IntAct, sourced
from interaction screens. Per curation guidelines, bare "protein binding" is
uninformative and should not be treated as core:
These IPI binding annotations are kept as non-core (or over-annotated); none establishes a
specific informative MF beyond what SH2/receptor-binding terms already capture.
PMID:9727029 ("Interaction of human SOCS-2 with the IGF-I receptor", Dey et al. 1998)
is the abstract title about SOCS-2, but UniProt lists Dey/Furlanetto/Nissley IGF1R work
for SOCS3 too (PubMed:11071852 is the SOCS3-IGF1R paper). The GOA IDA annotation
GO:0004860 protein kinase inhibitor activity / GO:0009898 cytoplasmic side of PM is
attributed to PMID:9727029 by UniProt curators. Per CLAUDE.md, do NOT REMOVE an
experimental (IDA) annotation merely because the cached abstract foregrounds a paralog
(SOCS2) β the function (kinase inhibitor activity, plasma-membrane-proximal action) is
correct for SOCS3. The MF protein kinase inhibitor activity is independently strongly
supported (KIR mechanism, ISS GO:0019210). ACCEPT GO:0004860 as core; the cellular
component GO:0009898 cytoplasmic side of plasma membrane is consistent with SOCS3
acting at receptor tails β keep as non-core location.
GO:0035198 miRNA binding (IEA, Ensembl ortholog transfer from mouse O35718): no strong
human evidence; SOCS3 is not a recognized RNA-binding/miRNA-binding protein. SOCS3 is
itself a miRNA target (e.g. miR-221, PMID:25019494), which is the opposite relationship.
This looks like an erroneous ortholog-transferred annotation β MARK_AS_OVER_ANNOTATED.
GO:0097398 cellular response to IL-17 (IEA ortholog transfer): plausible (SOCS3 is
induced by/feeds back on IL-17-related inflammation) but indirect; keep as non-core.
PMID:25019494 (miR-221 downregulates SOCS1/SOCS3): IMP for GO:0046426 negative
regulation of JAK-STAT. The paper shows miR-221 represses SOCS3 to enhance IFN/JAK/STAT
anti-HCV effect, confirming SOCS3 as a JAK-STAT inhibitor whose loss prolongs signaling.
Supports the negative-regulation-of-JAK-STAT function. ACCEPT (core process).
Validation note: core_functions MF ids are strictly validated; supporting_text must be a
verbatim substring of the cited cached publication.
id: O14543
gene_symbol: SOCS3
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
SOCS3 (Suppressor of cytokine signaling 3; also CIS-3, SSI-3) is a 225-residue
cytoplasmic adaptor protein and a cytokine-inducible negative-feedback inhibitor
of JAK-STAT signaling. It has a modular architecture comprising an N-terminal
kinase inhibitory region (KIR, ~residues 22-33), an extended SH2 subdomain (ESS),
a central SH2 domain (~residues 46-142), and a C-terminal SOCS box (~residues
177-224). Through its SH2 domain SOCS3 docks onto specific phosphotyrosine motifs
on activated cytokine receptors, most notably gp130/IL6ST, but also LIFR, EPOR,
the leptin receptor (LEPR), IL12RB2, CSF3R/G-CSF receptor and the insulin/IGF-I
receptors, and onto activated JAK2. The KIR then acts as a pseudosubstrate that
occupies the JAK catalytic groove and inhibits JAK kinase activity, blocking
downstream STAT (especially STAT3) phosphorylation. Through its SOCS box SOCS3
recruits the Elongin B/C-Cullin5-RBX2 (ECS) module, functioning as the
substrate-recognition subunit of a Cullin5-RING E3 ubiquitin ligase that targets
bound receptor/JAK components for ubiquitination and proteasomal degradation.
SOCS3 is transcriptionally induced by STAT3 (and other cytokine signals),
establishing a classical negative-feedback loop. It is a principal physiological
brake on IL-6 and leptin signaling and modulates erythropoiesis, immune and
inflammatory responses (including Th17 biology), and metabolic signaling.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000041
title: Gene Ontology annotation based on UniPathway vocabulary mapping
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: PMID:12754505
title: SOCS3 negatively regulates IL-6 signaling in vivo.
findings:
- statement: SOCS3 is the principal physiological negative regulator of IL-6/gp130
signaling in vivo; conditional Socs3 deletion prolongs STAT1 and STAT3 activation
after IL-6 stimulation, whereas IFN-gamma responses are SOCS1-dependent.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: PubMed-verified (Croker et al., Nat Immunol 2003). Abstract directly
supports the in vivo IL-6-specific JAK-STAT negative-regulation role; basis
for the mouse-ortholog ISS transfers.
- id: PMID:19027008
title: The role of microtubule-associated protein 1S in SOCS3 regulation of IL-6
signaling.
findings:
- statement: MAP1S was identified as a novel SOCS3-interacting protein; the SOCS3-MAP1S
interaction and microtubule integrity contribute to SOCS3 inhibition of IL-6/STAT3
signaling.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified; genuinely about SOCS3. Supports a specific binding
partner (MAP1S/Q66K74) but the GOA annotation is generic 'protein binding'.
- id: PMID:24728074
title: Enhanced prediction of Src homology 2 (SH2) domain binding potentials using
a fluorescence polarization-derived c-Met, c-Kit, ErbB, and androgen receptor
interactome.
findings:
- statement: High-throughput fluorescence-polarization SH2-domain interactome study;
reports SOCS3 SH2 binding to phosphopeptides including c-Kit (KIT) and c-Met
(MET).
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified methodological/proteomics paper. Source of generic
'protein binding' IPI annotations (KIT, MET); not gene-function-defining.
- id: PMID:25019494
title: MiR-221 accentuates IFNΧ³s anti-HCV effect by downregulating SOCS1 and SOCS3.
findings:
- statement: SOCS3 (with SOCS1) is a well-established inhibitor of the IFN/JAK/STAT
pathway; miR-221 downregulates SOCS3, relieving JAK-STAT inhibition and enhancing
the anti-HCV effect of IFN-alpha.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified. Supports SOCS3 as a negative regulator of JAK-STAT
(loss prolongs/enhances signaling); cited as IMP for GO:0046426.
- id: PMID:25203322
title: PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates
epithelial-mesenchymal transition and metastasis.
findings:
- statement: Reports a SOCS3-SNAI1 protein-protein interaction (IntAct) within an
EMT/SNAIL-degradation study primarily focused on FBXO11.
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified. The paper's focus is FBXO11/SNAIL; SOCS3 appears
only as an interaction partner. Source of a generic 'protein binding' annotation.
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings:
- statement: Systematic binary (Y2H) interactome map reporting SOCS3 interactions
(e.g., YES1, KIAA1958).
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified high-throughput interactome (Rolland et al. 2014).
Source of generic 'protein binding' IPI annotations; not function-defining.
- id: PMID:27893700
title: Trans-presentation of IL-6 by dendritic cells is required for the priming
of pathogenic T(H)17 cells.
findings:
- statement: IL-6 trans-presentation by dendritic cells drives priming of pathogenic
Th17 cells; SOCS3 is a feedback inhibitor within the IL-6/STAT3/Th17 axis.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified, full text available. Supports the IL-6/Th17 context
cited as TAS for T-helper 17 cell lineage commitment.
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings:
- statement: Reference binary (Y2H) interactome map reporting SOCS3 interactions
(e.g., YES1, TXK, BLK, KIAA1958).
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified high-throughput interactome (Luck et al. 2020).
Source of generic 'protein binding' IPI annotations; not function-defining.
- id: PMID:9266833
title: 'Cloning and functional analysis of new members of STAT induced STAT inhibitor
(SSI) family: SSI-2 and SSI-3.'
findings:
- statement: Cloning paper for human SSI-2 (SOCS2) and SSI-3 (SOCS3); SSI family
members are cytokine-induced and act in negative feedback control of JAK-STAT
signaling. Forced expression of SSI-3/SOCS3 suppressed the apoptotic effect
of LIF.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: PubMed-verified. SSI-3 = SOCS3; correctly cited. Abstract supports
JAK-STAT inhibition and suppression of LIF-induced apoptosis (basis of TAS annotations).
- id: PMID:9727029
title: Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like
growth factor-I receptor.
findings:
- statement: SOCS family proteins are negative regulators of cytokine receptor signaling
via the JAK/STAT pathway and interact with activated receptor tyrosine kinases
(here IGF-IR).
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified. Abstract title foregrounds SOCS-2, but UniProt
curators attribute the IDA protein-kinase-inhibitor-activity / plasma-membrane
annotations for SOCS3 to this reference; per guidelines the kinase-inhibitor
function is correct for SOCS3 and the experimental annotation is retained.
- id: PMID:15601820
title: VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1
and Cul5-Rbx2 modules of ubiquitin ligases.
findings:
- statement: SOCS-box proteins (including SOCS3) recruit substrates to the ECS
(Elongin B/C-Cullin-Rbx) complex via Elongin B/C and associate specifically
with Cul5-Rbx2, defining the SOCS-box E3 ubiquitin ligase module.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: PubMed-verified (Kamura et al. 2004). Establishes the SOCS-box ->
Elongin BC -> Cul5-Rbx2 E3 ligase substrate-recognition mechanism underlying
SOCS3 ubiquitin-ligase function.
- id: Reactome:R-HSA-1112755
title: SOCS3 binds IL6ST
findings: []
- id: Reactome:R-HSA-6785860
title: Expression of SOCS1
findings: []
- id: Reactome:R-HSA-6790041
title: Expression of STAT3-upregulated cytosolic proteins
findings: []
- id: Reactome:R-HSA-877269
title: SOCS-1 and SOCS-3 binds to p-JAK2
findings: []
- id: Reactome:R-HSA-8848110
title: SOCS3 binds activated PTK6
findings: []
- id: Reactome:R-HSA-8848178
title: STAT3 stimulates SOCS3 expression
findings: []
- id: Reactome:R-HSA-8952039
title: NEDD8:AcM-UBE2F binds CRL5 E3 ubiquitin ligase complex
findings: []
- id: Reactome:R-HSA-8952044
title: AcM-UBE2F transfers NEDD8 to CRL5 E3 ubiquitin ligase complex
findings: []
- id: Reactome:R-HSA-8955241
title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
findings: []
- id: Reactome:R-HSA-8955289
title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
findings: []
- id: Reactome:R-HSA-8956040
title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
findings: []
- id: Reactome:R-HSA-9705738
title: SOCS1,3 ubiquitinates CSF3R in SOCS1,3:p-4Y-CSF3R:CSF3 dimer:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2:CUL5:ELOB:ELOC:RNF7
findings: []
- id: Reactome:R-NUL-1169195
title: SOCS binding to Ghr
findings: []
existing_annotations:
- term:
id: GO:0046426
label: negative regulation of receptor signaling pathway via JAK-STAT
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Phylogenetic (IBA) annotation to the defining SOCS3 process - negative
feedback inhibition of JAK-STAT signaling. This is the central, well-supported
biological role of SOCS3 and matches experimental (IMP) and ISS evidence.
action: ACCEPT
reason: Core function of SOCS3; concordant with experimental and orthology evidence
across the SOCS family.
- term:
id: GO:0005126
label: cytokine receptor binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: SOCS3 SH2 domain docks onto phosphotyrosine motifs of activated cytokine
receptors (gp130/IL6ST, LIFR, EPOR, LEPR, IL12RB2, CSF3R). Cytokine receptor
binding captures this receptor-docking molecular function.
action: ACCEPT
reason: Well-supported SH2-mediated receptor docking; a core molecular activity
enabling SOCS3 to act at receptor complexes.
- term:
id: GO:0019221
label: cytokine-mediated signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: SOCS3 acts within cytokine-mediated signaling pathways as a feedback
inhibitor. The term is correct but high-level; the negative-regulation term
(GO:0046426) is the more informative process annotation.
action: KEEP_AS_NON_CORE
reason: Correct but general process context; the specific negative-regulation-of-JAK-STAT
term better represents the core role.
- term:
id: GO:0035556
label: intracellular signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Generic InterPro-derived process annotation. SOCS3 indeed participates
in intracellular signal transduction, but this is non-specific relative to its
JAK-STAT negative-regulation role.
action: KEEP_AS_NON_CORE
reason: Correct but uninformative high-level process; superseded by more specific
JAK-STAT terms.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19027008
qualifier: enables
review:
summary: IntAct binding annotation for the SOCS3-MAP1S interaction. 'Protein binding'
is uninformative as a molecular function; the specific partner (MAP1S) is captured
in the reference findings.
action: KEEP_AS_NON_CORE
reason: Per curation guidelines, generic GO:0005515 'protein binding' is not a
core informative MF; valid interaction evidence but kept non-core.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24728074
qualifier: enables
review:
summary: SH2-domain interactome screen reporting SOCS3 binding to phosphopeptides
(e.g., KIT, MET). Generic 'protein binding' molecular function.
action: KEEP_AS_NON_CORE
reason: Generic protein-binding from a high-throughput SH2 screen; not a core
informative MF.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25203322
qualifier: enables
review:
summary: SOCS3-SNAI1 interaction reported in an EMT study focused on FBXO11/SNAIL.
Generic 'protein binding' annotation.
action: KEEP_AS_NON_CORE
reason: Generic protein-binding; not a core informative MF for SOCS3.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
qualifier: enables
review:
summary: Interactions from a proteome-scale binary interactome map (e.g., YES1,
KIAA1958). Generic 'protein binding'.
action: KEEP_AS_NON_CORE
reason: High-throughput Y2H protein-binding; not a core informative MF.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: Interactions from the reference human binary interactome map (e.g., YES1,
TXK, BLK). Generic 'protein binding'.
action: KEEP_AS_NON_CORE
reason: High-throughput Y2H protein-binding; not a core informative MF.
- term:
id: GO:0001784
label: phosphotyrosine residue binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: SOCS3 SH2 domain recognizes phosphotyrosine motifs on activated receptors
and JAK2; phosphotyrosine residue binding is a precise, mechanistically grounded
molecular function for the SH2 module.
action: ACCEPT
reason: Accurate and informative MF capturing SH2-mediated pTyr recognition; a
core docking activity.
- term:
id: GO:0035198
label: miRNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: Ortholog-transferred (Ensembl Compara, from mouse O35718) miRNA-binding
annotation. SOCS3 is not an established RNA/miRNA-binding protein; rather it
is itself a target of miRNAs (e.g., miR-221). This appears to be an erroneous
electronic transfer.
action: MARK_AS_OVER_ANNOTATED
reason: No credible evidence SOCS3 binds miRNA; likely spurious ortholog transfer,
possibly confusing SOCS3-as-miRNA-target with miRNA binding.
- term:
id: GO:0097398
label: cellular response to interleukin-17
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Ortholog-transferred process annotation. SOCS3 is plausibly involved
in IL-17-related inflammatory responses, but the link is indirect and not central
to its molecular function.
action: KEEP_AS_NON_CORE
reason: Plausible but indirect process from electronic transfer; not a core function.
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: IEA
original_reference_id: GO_REF:0000041
qualifier: involved_in
review:
summary: SOCS3 is the substrate-recognition subunit of an Elongin BC-Cullin5-RBX2
(ECS) E3 ubiquitin ligase via its SOCS box, mediating ubiquitination of bound
receptor/JAK components. Protein ubiquitination is a correct and core process.
action: ACCEPT
reason: Core SOCS-box-mediated function; concordant with mechanistic literature
(Kamura et al. 2004) and Reactome CSF3R/CRL5 ubiquitination events.
- term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: ISS (from mouse ortholog) placing SOCS3 in JAK-STAT signaling. SOCS3's
role is specifically negative regulation of this pathway; the parent 'involved_in
JAK-STAT' is correct but less informative than GO:0046426.
action: KEEP_AS_NON_CORE
reason: Correct pathway context but the negative-regulation term is the core,
more informative annotation.
- term:
id: GO:0019210
label: kinase inhibitor activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
summary: SOCS3 inhibits JAK tyrosine kinase activity via its KIR (pseudosubstrate)
and SH2 domain. Kinase inhibitor activity is correct; the more specific child
term protein kinase inhibitor activity (GO:0004860) is preferred and is independently
annotated (IDA/TAS).
action: MODIFY
reason: Generalize to the more specific, experimentally supported protein kinase
inhibitor activity.
proposed_replacement_terms:
- id: GO:0004860
label: protein kinase inhibitor activity
- term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
evidence_type: ISS
original_reference_id: PMID:12754505
qualifier: involved_in
review:
summary: ISS from mouse Socs3, supported by in vivo evidence that Socs3 loss prolongs
IL-6-induced STAT activation. Correct pathway context but less informative than
the negative-regulation term.
action: KEEP_AS_NON_CORE
reason: Correct but general; negative-regulation-of-JAK-STAT is the core annotation.
- term:
id: GO:0019210
label: kinase inhibitor activity
evidence_type: ISS
original_reference_id: PMID:12754505
qualifier: enables
review:
summary: Kinase-inhibitor MF transferred by similarity. As above, the specific
protein kinase inhibitor activity term is preferred and is experimentally supported.
action: MODIFY
reason: Generalize/refine to the more specific protein kinase inhibitor activity
term.
proposed_replacement_terms:
- id: GO:0004860
label: protein kinase inhibitor activity
- term:
id: GO:0070102
label: interleukin-6-mediated signaling pathway
evidence_type: ISS
original_reference_id: PMID:12754505
qualifier: involved_in
review:
summary: SOCS3 is the dominant feedback inhibitor of IL-6/gp130 signaling in vivo
(Croker et al. 2003); involvement in the IL-6-mediated signaling pathway is
well-supported and biologically central.
action: ACCEPT
reason: Strongly supported, specific, and central to SOCS3 biology (IL-6 brake).
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785860
qualifier: is_active_in
review:
summary: SOCS3 acts in the cytosol and at the cytoplasmic face of receptor complexes.
Cytosolic localization is correct but is a general location, not a core function.
action: KEEP_AS_NON_CORE
reason: Correct subcellular location; one of many redundant Reactome cytosol annotations.
- term:
id: GO:0072540
label: T-helper 17 cell lineage commitment
evidence_type: TAS
original_reference_id: PMID:27893700
qualifier: involved_in
review:
summary: SOCS3 modulates the IL-6/STAT3 axis that drives Th17 differentiation;
this is a downstream physiological/developmental consequence rather than SOCS3's
molecular core function.
action: KEEP_AS_NON_CORE
reason: Valid process context (IL-6/Th17 axis) but a pleiotropic, downstream role,
not core.
- term:
id: GO:0004860
label: protein kinase inhibitor activity
evidence_type: IDA
original_reference_id: PMID:9727029
qualifier: enables
review:
summary: Direct-assay annotation for SOCS3 protein kinase inhibitor activity. SOCS3
inhibits JAK tyrosine kinase via its KIR/SH2 modules. Although the cached abstract
title names SOCS-2/IGF-IR, this is the curator-assigned experimental evidence
for SOCS3 kinase-inhibitor activity and the function is correct for SOCS3.
action: ACCEPT
reason: Core molecular function of SOCS3 (KIR-mediated JAK inhibition); per guidelines
an experimental annotation is not removed on the basis of an abstract-only paralog
title.
- term:
id: GO:0009898
label: cytoplasmic side of plasma membrane
evidence_type: IDA
original_reference_id: PMID:9727029
qualifier: is_active_in
review:
summary: SOCS3 is recruited to phosphorylated receptor cytoplasmic tails at the
inner face of the plasma membrane, consistent with this location. Accurate but
a location, not a core molecular function.
action: KEEP_AS_NON_CORE
reason: Correct site of action (receptor tails at the membrane); supporting location
rather than core function.
- term:
id: GO:0046426
label: negative regulation of receptor signaling pathway via JAK-STAT
evidence_type: IMP
original_reference_id: PMID:25019494
qualifier: involved_in
review:
summary: Experimental (IMP) support that modulating SOCS3 levels (via miR-221)
alters JAK-STAT signaling output - downregulating SOCS3 relieves inhibition
and enhances IFN/JAK/STAT signaling. Confirms SOCS3 as a negative regulator
of JAK-STAT.
action: ACCEPT
reason: Core function; experimentally supported negative regulation of JAK-STAT
signaling.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1112755
qualifier: located_in
review:
summary: Reactome cytosol localization (SOCS3 binds IL6ST). Correct location annotation.
action: KEEP_AS_NON_CORE
reason: Correct subcellular location; redundant with other cytosol annotations.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6790041
qualifier: located_in
review:
summary: Reactome cytosol localization annotation. Correct but redundant.
action: KEEP_AS_NON_CORE
reason: Correct location; one of many redundant Reactome cytosol annotations.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-877269
qualifier: located_in
review:
summary: Reactome cytosol localization (SOCS-1/SOCS-3 bind p-JAK2). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8848110
qualifier: located_in
review:
summary: Reactome cytosol localization (SOCS3 binds activated PTK6). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8848178
qualifier: located_in
review:
summary: Reactome cytosol localization (STAT3 stimulates SOCS3 expression). Correct
location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8952039
qualifier: located_in
review:
summary: Reactome cytosol localization (CRL5/neddylation pathway). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8952044
qualifier: located_in
review:
summary: Reactome cytosol localization (CRL5/neddylation pathway). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8955241
qualifier: located_in
review:
summary: Reactome cytosol localization (CAND1/CRL regulation). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8955289
qualifier: located_in
review:
summary: Reactome cytosol localization (COMMD/CAND1/CRL regulation). Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8956040
qualifier: located_in
review:
summary: Reactome cytosol localization (COP9 signalosome deneddylation). Correct
location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9705738
qualifier: located_in
review:
summary: Reactome cytosol localization (SOCS1,3 ubiquitinates CSF3R within a CUL5/ELOB/ELOC/RNF7
complex). Correct location and consistent with SOCS3 E3-ligase function.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-NUL-1169195
qualifier: located_in
review:
summary: Reactome cytosol localization (SOCS binding to growth hormone receptor).
Correct location.
action: KEEP_AS_NON_CORE
reason: Correct location; redundant Reactome cytosol annotation.
- term:
id: GO:0004860
label: protein kinase inhibitor activity
evidence_type: TAS
original_reference_id: PMID:9266833
qualifier: enables
review:
summary: TAS annotation for SOCS3 (SSI-3) protein kinase inhibitor activity from
the SSI-2/SSI-3 cloning/functional paper. Concordant with the IDA and ISS kinase-inhibitor
annotations; reflects KIR-mediated JAK inhibition.
action: ACCEPT
reason: Core molecular function; corroborates the protein kinase inhibitor activity
of SOCS3.
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: TAS
original_reference_id: PMID:9266833
qualifier: involved_in
review:
summary: Based on forced SSI-3/SOCS3 expression suppressing the apoptotic effect
of LIF in M1 myeloid cells. This is an indirect, downstream consequence of blocking
LIF/gp130/STAT3 signaling rather than a direct anti-apoptotic molecular activity,
and is context-dependent (SOCS3 can be pro- or anti-apoptotic depending on cell
type).
action: KEEP_AS_NON_CORE
reason: Indirect, context-dependent downstream effect of JAK-STAT inhibition;
retained but not a core function.
core_functions:
- description: SH2-mediated docking of SOCS3 onto phosphotyrosine motifs of activated
cytokine receptors and JAK2, positioning SOCS3 at the receptor/kinase complex.
supported_by:
- reference_id: PMID:9266833
supporting_text: we identified two novel human genes which products have homologous
region in their SH2 domain and its COOH-terminal region to mouse SSI-1
- reference_id: PMID:12754505
supporting_text: Members of the suppressor of cytokine signaling (SOCS) family
are potentially key physiological negative regulators of interleukin-6 (IL-6)
signaling.
molecular_function:
id: GO:0001784
label: phosphotyrosine residue binding
directly_involved_in:
- id: GO:0019221
label: cytokine-mediated signaling pathway
locations:
- id: GO:0009898
label: cytoplasmic side of plasma membrane
- description: KIR/SH2-mediated inhibition of JAK tyrosine kinase activity, blocking
downstream STAT phosphorylation as the catalytic core of SOCS3 negative feedback.
supported_by:
- reference_id: PMID:9266833
supporting_text: Northern blotting analysis and functional studies demonstrated
that SSI-2 and SSI-3 mRNA were also induced by cytokine stimulation and their
forced expression in mouse myeloid leukemia cell, M1, suppressed the apoptotic
effect of LIF, like SSI-1.
molecular_function:
id: GO:0004860
label: protein kinase inhibitor activity
directly_involved_in:
- id: GO:0046426
label: negative regulation of receptor signaling pathway via JAK-STAT
- description: Substrate-recognition subunit of an Elongin BC-Cullin5-RBX2 (ECS) E3
ubiquitin ligase that, via the SOCS box, targets bound receptor/JAK components
for ubiquitination and proteasomal degradation.
supported_by:
- reference_id: PMID:15601820
supporting_text: The ECS (Elongin B/C-Cul2/Cul5-SOCS-box protein) complex is a
member of a family of ubiquitin ligases that share a Cullin-Rbx module.
- reference_id: PMID:15601820
supporting_text: SOCS-box proteins recruit substrates to the ECS complex and are
linked to Cullin-Rbx via Elongin B/C.
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
contributes_to_molecular_function:
id: GO:0061659
label: ubiquitin-like protein ligase activity
directly_involved_in:
- id: GO:0016567
label: protein ubiquitination
- description: Negative-feedback inhibition of cytokine receptor signaling through
the JAK-STAT pathway, the integrative core role of SOCS3 (principal brake on IL-6/gp130
signaling).
supported_by:
- reference_id: PMID:12754505
supporting_text: Socs3 deficiency results in prolonged activation of signal transducer
and activator of transcription 1 (STAT1) and STAT3 after IL-6 stimulation but
normal activation of STAT1 after stimulation with interferon-gamma (IFN-gamma).
- reference_id: PMID:9266833
supporting_text: SSI-1 is thought to play a critical role in negative feedback
control of JAK-STAT signaling pathway.
molecular_function:
id: GO:0004860
label: protein kinase inhibitor activity
directly_involved_in:
- id: GO:0046426
label: negative regulation of receptor signaling pathway via JAK-STAT
- id: GO:0070102
label: interleukin-6-mediated signaling pathway
suggested_questions:
- question: To what extent does SOCS3-mediated ubiquitination/proteasomal degradation
of receptor complexes (via the Cul5 ECS ligase) contribute to signal termination
versus the direct KIR-mediated kinase-inhibition mechanism, and are these separable
in vivo?
- question: Which receptor phosphotyrosine motifs and JAK isoforms are the physiologically
dominant SOCS3 targets in different tissues (liver, adipose, immune cells)?
suggested_experiments:
- description: Separation-of-function mutants (KIR-dead vs SOCS-box-dead vs SH2-dead)
expressed at endogenous levels, assayed for IL-6/gp130 STAT3 signaling kinetics
and receptor/JAK ubiquitination, to dissect the relative contribution of kinase
inhibition versus E3-ligase-mediated degradation.
- description: Quantitative proteomics (ubiquitinome/degradomics) in SOCS3-null versus
reconstituted cells after IL-6/EPO/leptin stimulation to identify the physiological
SOCS3 ECS-ligase substrates.