id: O15524
gene_symbol: SOCS1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SOCS1 (Suppressor of cytokine signaling 1; also JAB/SSI-1) is a cytokine-inducible
  intracellular protein that acts as a potent negative-feedback inhibitor of JAK-STAT
  signaling, with a particularly essential role in limiting type I and type II interferon
  (especially IFN-gamma) responses, as well as IL2, IL4, IL6 and LIF signaling. It has a
  modular architecture comprising an N-terminal kinase inhibitory region (KIR), an
  extended SH2 subdomain (ESS), a central SH2 domain, and a C-terminal SOCS box. SOCS1
  docks through its SH2 domain onto phosphotyrosine in the activation loop of receptor-
  associated Janus kinases (JAK1, JAK2 and TYK2), while its KIR acts as a pseudosubstrate
  that occludes the kinase substrate-binding groove, thereby directly inhibiting JAK
  catalytic activity and downstream STAT phosphorylation. Through its SOCS box, SOCS1
  recruits the Elongin BC complex and a Cullin (CUL2/CUL5)/RBX1 scaffold to form an ECS
  (Elongin BC-Cullin-SOCS box) E3 ubiquitin ligase in which SOCS1 serves as the substrate-
  recognition subunit, targeting bound proteins (such as JAK2, IRS proteins and NF-kB
  RelA) for polyubiquitination and proteasomal degradation. SOCS1 thereby contributes to
  the termination of cytokine signaling and to immune homeostasis; it acts as a tumor
  suppressor and its loss or haploinsufficiency causes interferon-driven autoinflammatory
  and autoimmune disease.
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:16273093
  title: A quantitative protein interaction network for the ErbB receptors using protein
    microarrays.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale SH2/PTB protein-microarray network for ErbB receptors. Supports a
      generic SOCS1-ERBB2 (P04626) protein interaction (GO:0005515), not a focused
      SOCS1 functional study. Peripheral to SOCS1 physiology.
- id: PMID:16643902
  title: The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation
    of SOCS6 associated proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Primarily about SOCS6/HOIL-1. The IntAct interaction underlying the SOCS1
      GO:0005515 annotation is with ELOC (Q15369). The paper does state the shared
      SOCS-box principle that all SOCS proteins bind an Elongin BC E3 complex through
      the common SOCS-box, consistent with SOCS1's Elongin-BC adaptor role.
- id: PMID:17183367
  title: COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing
    ubiquitin ligase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Demonstrates an ECS(SOCS1) E3 ligase containing Elongins B/C, Cul2 and SOCS1 that
      ubiquitinates NF-kB RelA, with SOCS1 binding RelA as substrate. Strong support for
      SOCS1's SOCS-box ubiquitin-ligase substrate-recognition adaptor function, although
      the GOA annotation it backs is the generic GO:0005515 protein binding.
- id: PMID:18172216
  title: SOCS1 is an inducible host factor during HIV-1 infection and regulates the
    intracellular trafficking and stability of HIV-1 Gag.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text confirms SOCS1 directly binds HIV-1 Gag via its SH2 domain and that the
      SOCS box is required for Gag particle production. Host-pathogen interaction;
      supports GO:0005515 with gag (Q77YG1) but is not part of SOCS1's core cellular
      physiology.
- id: PMID:22387553
  title: Downregulation of inflammatory microRNAs by Ig-like transcript 3 is essential
    for the differentiation of human CD8(+) T suppressor cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: >-
      SOCS1 appears as a direct miR-155 target in ILT3-induced CD8+ T suppressor cells.
      The abstract does not establish a direct SOCS1 role in regulatory T cell
      differentiation; the IMP annotation to GO:0045591 rests on full text not in cache.
- id: PMID:23401859
  title: DCNL1 functions as a substrate sensor and activator of cullin 2-RING ligase.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      DCNL1/CUL2 neddylation study; SOCS1 is used as an ECS(SOCS1)/CRL2 component context.
      Supports the generic GO:0005515 interaction (DCUN1D1) and is consistent with
      SOCS1's CRL2/CRL5 substrate-receptor role.
- id: PMID:25019494
  title: MiR-221 accentuates IFN's anti-HCV effect by downregulating SOCS1 and SOCS3.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Identifies SOCS1 (and SOCS3) as miR-221 targets and explicitly describes them as
      well established inhibitory factors on the IFN/JAK/STAT pathway, consistent with
      SOCS1's core negative regulation of JAK-STAT signaling.
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale AP-MS EGFR-network rewiring study; underlies a generic SOCS1-ELOC
      (Q15369) interaction (GO:0005515). Not a focused SOCS1 functional characterization.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI all-by-all binary interactome; supports a generic SOCS1-SH3GL1 (Q99961)
      interaction (GO:0005515). High-throughput, context-free.
- id: PMID:32634427
  title: Downregulation of microRNA-155-5p prevents immune thrombocytopenia by promoting
    macrophage M2 polarization via the SOCS1-dependent PD1/PDL1 pathway.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      SOCS1 is a validated miR-155-5p target; its up-regulation promotes macrophage M2
      polarization via PD1/PDL1 in an ITP model. Supports a contextual role in macrophage
      polarization (IMP, GO:0030225) rather than a core SOCS1 molecular function.
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions
    in cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Cancer neoPPI BRET screen; underlies a generic SOCS1-SMAD4 (Q13485) interaction
      (GO:0005515). High-throughput screen, not a focused SOCS1 study.
- id: PMID:9202125
  title: A family of cytokine-inducible inhibitors of signalling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding SOCS1 paper (Starr et al., Nature 1997). Cloned SOCS-1 by its ability to
      inhibit IL6-induced macrophage differentiation; SOCS-1 inhibits IL6-induced
      receptor phosphorylation and STAT activation and acts in a classic negative-
      feedback loop. Direct support for the protein kinase inhibitor / JAK-STAT negative
      regulation core functions.
- id: PMID:9202126
  title: A new protein containing an SH2 domain that inhibits JAK kinases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding SOCS1/JAB paper (Endo et al., Nature 1997). Shows JAB binds the JAK2 JH1
      kinase domain and that interaction with Jak1/Jak2/Jak3 markedly reduces their
      tyrosine-kinase activity and suppresses STAT phosphorylation/activation. Direct
      support for JAK binding and kinase inhibition.
- id: PMID:9727029
  title: Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like
    growth factor-I receptor.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Principally about SOCS-2, but the abstract explicitly states that hSOCS-1 protein
      also interacted strongly with IGF-IR in the two-hybrid assay, supporting the SOCS1
      IGF1R-binding (GO:0005159) and protein kinase binding (GO:0019901) IPI annotations.
      The NAS GO:0046426 here is a by-analogy assertion.
- id: Reactome:R-HSA-6785860
  title: Expression of SOCS1
  findings: []
- id: Reactome:R-HSA-877269
  title: SOCS-1 and SOCS-3 binds to p-JAK2
  findings: []
- id: Reactome:R-HSA-8983011
  title: Expression of STAT5 upregulated genes
  findings: []
- id: Reactome:R-HSA-9705738
  title: SOCS1,3 ubiquitinates CSF3R in SOCS1,3:p-4Y-CSF3R:CSF3 dimer complex
  findings: []
- id: Reactome:R-NUL-1169195
  title: SOCS binding to Ghr
  findings: []
core_functions:
- description: >-
    SOCS1 is a direct inhibitor of Janus kinase catalytic activity. It binds receptor-
    associated JAK1, JAK2 and TYK2 (via its SH2 domain docking onto phosphotyrosine in
    the JAK activation loop, with its kinase inhibitory region (KIR) acting as a
    pseudosubstrate that blocks the kinase substrate-binding groove), markedly reducing
    JAK tyrosine-kinase activity and suppressing downstream STAT phosphorylation and
    activation.
  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
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:9202126
    supporting_text: "Interaction of JAB with Jak1, Jak2 or Jak3 markedly reduces their tyrosine-kinase activity and suppresses the tyrosine-phosphorylation and activation of STATs."
  - reference_id: PMID:9202125
    supporting_text: "Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation."
- description: >-
    SOCS1 binds activated Janus kinases through its SH2 domain, recognizing
    phosphotyrosine within the JAK JH1 (kinase) domain. This phosphotyrosine-dependent
    docking onto the activated kinase is the prerequisite for kinase inhibition and for
    delivering bound substrates to the ubiquitination machinery.
  molecular_function:
    id: GO:0019901
    label: protein kinase binding
  directly_involved_in:
  - id: GO:0046426
    label: negative regulation of receptor signaling pathway via JAK-STAT
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:9202126
    supporting_text: "JAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain"
- description: >-
    Through its C-terminal SOCS box, SOCS1 recruits the Elongin BC complex and a
    Cullin (CUL2/CUL5)/RBX1 scaffold to assemble an ECS (Elongin BC-Cullin-SOCS box)
    E3 ubiquitin ligase, acting as the substrate-recognition subunit that brings bound
    target proteins to the ligase for polyubiquitination and subsequent proteasomal
    degradation (e.g. NF-kB RelA in the ECS(SOCS1) complex).
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  directly_involved_in:
  - id: GO:0016567
    label: protein ubiquitination
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:17183367
    supporting_text: "COMMD1 accelerates the ubiquitination and degradation of NF-kappaB subunits through its interaction with a multimeric ubiquitin ligase containing Elongins B and C, Cul2 and SOCS1 (ECS(SOCS1))."
  - reference_id: PMID:16643902
    supporting_text: "All SOCS proteins bind an Elongin BC E3 ubiquitin ligase complex through the common Socs-box."
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: >-
      Phylogenetically inferred negative regulation of JAK-STAT signaling. This is the
      central, defining function of SOCS1, supported by the founding experimental papers
      and conserved across orthologs.
    action: ACCEPT
    reason: >-
      Core SOCS1 function; consistent with experimental evidence (PMID:9202125,
      PMID:9202126) and conserved across the SOCS1 family.
- term:
    id: GO:0005126
    label: cytokine receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred cytokine receptor binding. SOCS1 docks onto activated
      cytokine receptor / JAK complexes via its SH2 domain (e.g. IFNGR1), so binding to
      receptor components is plausible, but the informative molecular function is its
      kinase binding/inhibition rather than receptor binding per se.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with SH2-mediated docking onto receptor complexes, but secondary to the
      core kinase-inhibitor / ubiquitin-adaptor functions.
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SOCS1 acts within cytokine-mediated signaling pathways as a negative-feedback
      regulator. Accurate but general; the more specific term is negative regulation of
      JAK-STAT signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but high-level; the negative-regulation JAK-STAT term captures the core
      role more precisely.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic subcellular-location annotation. SOCS1 is detected in the nucleus and
      has reported nuclear activities (e.g. targeting nuclear RelA/p53), but its primary
      site of action is the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by UniProt subcellular location (PubMed:16410555); non-core relative to
      cytoplasmic JAK regulation.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic location annotation reflecting detection in perinuclear cytoplasmic
      vesicles upon interaction with FGFR3. Condition-specific localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by UniProt (PubMed:16410555) but condition-specific and non-core.
- term:
    id: GO:0032502
    label: developmental process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Very general ARBA-derived developmental-process annotation. Uninformative for
      SOCS1's specific function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Root-level/very general term with no specific support; over-annotation.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-derived general signal-transduction annotation. SOCS1 indeed acts in
      intracellular signaling, but as a negative regulator; the term is high-level.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but very general; superseded by the specific JAK-STAT negative-regulation
      term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16273093
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from an ErbB SH2/PTB protein-microarray network
      (interaction with ERBB2/P04626). Uninformative term per curation guidelines.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; high-throughput interaction not central to
      SOCS1 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16643902
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation (interaction with ELOC/Q15369). The
      SOCS1-Elongin C interaction is biologically real and underlies the SOCS-box E3
      adaptor function, but the GO term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Interaction is meaningful (Elongin C / SOCS-box) but the generic term does not
      convey the adaptor function captured in core_functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17183367
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation backing the ECS(SOCS1) complex with RelA/Elongin
      C/COMMD1. Biologically central to the ubiquitin-ligase adaptor role, but recorded
      under the uninformative 'protein binding' term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Underlying interaction supports the E3 substrate-adaptor core function; term itself
      is generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18172216
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation for the direct SOCS1-HIV-1 Gag interaction (via
      SOCS1 SH2). Host-pathogen interaction, not core cellular physiology.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real direct interaction but virus-related and peripheral; generic term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a large-scale KRAS/EGFR-network AP-MS study
      (interaction with ELOC/Q15369). Uninformative term, high-throughput context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; high-throughput interaction.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from the HuRI binary interactome (interaction
      with SH3GL1/Q99961). Uninformative term, context-free high-throughput screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; high-throughput interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a cancer neoPPI screen (interaction with
      SMAD4/Q13485). Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; high-throughput screen.
- term:
    id: GO:0019210
    label: kinase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Kinase inhibitor activity transferred from the mouse ortholog. Correct in essence;
      the more specific and experimentally supported term is protein kinase inhibitor
      activity (GO:0004860).
    action: MODIFY
    reason: >-
      Generalize-to-specific: SOCS1 specifically inhibits protein (tyrosine) kinases
      (JAKs); replace with protein kinase inhibitor activity.
    proposed_replacement_terms:
    - id: GO:0004860
      label: protein kinase inhibitor activity
- term:
    id: GO:0043372
    label: positive regulation of CD4-positive, alpha-beta T cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      T-cell differentiation role transferred electronically from the mouse ortholog
      (O35716). Consistent with SOCS1's role in T-cell homeostasis but not a core
      molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible from mouse ortholog; downstream immunophysiology, non-core.
- term:
    id: GO:0043377
    label: negative regulation of CD8-positive, alpha-beta T cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer from the mouse ortholog. Consistent with SOCS1's T-cell
      regulatory role; non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible from mouse ortholog; downstream immunophysiology, non-core.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-derived protein-ubiquitination annotation. Reflects SOCS1's SOCS-box E3
      ubiquitin ligase substrate-recognition role, which targets bound substrates for
      ubiquitination and proteasomal degradation.
    action: ACCEPT
    reason: >-
      Core process consistent with the ECS(SOCS1) E3 ligase adaptor function
      (PMID:17183367).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA) nucleoplasm localization. SOCS1 has documented
      nuclear pools and nuclear substrates; primary functional site remains cytoplasmic.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally observed location; non-core relative to cytoplasmic JAK regulation.
- term:
    id: GO:0030225
    label: macrophage differentiation
  evidence_type: IMP
  original_reference_id: PMID:32634427
  qualifier: involved_in
  review:
    summary: >-
      SOCS1 (a miR-155-5p target) promotes macrophage M2 polarization via the PD1/PDL1
      pathway in an immune thrombocytopenia model. Reflects a downstream contextual role
      in macrophage biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimental (IMP) but downstream/contextual; not a core molecular function.
      Defer to curator on the precise differentiation term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23401859
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a DCNL1/CUL2-neddylation study (with
      DCUN1D1/O14508). Consistent with SOCS1's CRL2/CRL5 substrate-receptor context but
      recorded under the uninformative 'protein binding' term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' is uninformative; interaction is contextual to CRL machinery.
- term:
    id: GO:0043372
    label: positive regulation of CD4-positive, alpha-beta T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse O35716) of the CD4 T-cell differentiation
      role; duplicates the IEA annotation above. Non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      By-similarity immunophysiology; non-core.
- term:
    id: GO:0043377
    label: negative regulation of CD8-positive, alpha-beta T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of the CD8 T-cell differentiation role; duplicates the
      IEA annotation. Non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      By-similarity immunophysiology; non-core.
- term:
    id: GO:0045591
    label: positive regulation of regulatory T cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:22387553
  qualifier: involved_in
  review:
    summary: >-
      Annotation from a study of ILT3-induced CD8+ T suppressor cell differentiation in
      which SOCS1 is a direct miR-155 target. The cached abstract does not clearly
      establish a direct SOCS1 role in regulatory T cell differentiation; the supporting
      detail is in full text not available here.
    action: UNDECIDED
    reason: >-
      Cannot verify the specific Treg-differentiation claim from the cached abstract;
      per guidelines use UNDECIDED rather than overruling the experimental annotation.
- 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 support: miR-221 downregulation of SOCS1/SOCS3 potentiates IFN's
      anti-HCV effect, with SOCS1/SOCS3 described as established inhibitors of the
      IFN/JAK/STAT pathway. Reinforces the core negative-regulation function.
    action: ACCEPT
    reason: >-
      Core JAK-STAT negative-regulation function, experimentally supported.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785860
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization (Reactome). SOCS1 acts on receptor-associated JAKs in the
      cytoplasm; this is its primary functional compartment.
    action: ACCEPT
    reason: >-
      Primary site of action; consistent across sources.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-877269
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization (Reactome), from the SOCS-1/SOCS-3 binding to p-JAK2 event.
      Consistent with the core cytoplasmic JAK-regulation role.
    action: ACCEPT
    reason: >-
      Primary functional compartment.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983011
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization (Reactome). Redundant with other cytosol annotations.
    action: ACCEPT
    reason: >-
      Consistent cytosolic localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9705738
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization (Reactome), from the SOCS1/3 CSF3R ubiquitination event.
      Consistent with the SOCS-box E3 adaptor activity occurring in the cytoplasm.
    action: ACCEPT
    reason: >-
      Consistent cytosolic localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-1169195
  qualifier: located_in
  review:
    summary: >-
      Cytosolic localization (Reactome). Redundant cytosol annotation.
    action: ACCEPT
    reason: >-
      Consistent cytosolic localization.
- term:
    id: GO:0019210
    label: kinase inhibitor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of kinase inhibitor activity. As with the IEA version,
      the specific supported term is protein kinase inhibitor activity (GO:0004860).
    action: MODIFY
    reason: >-
      Generalize-to-specific: replace with protein kinase inhibitor activity.
    proposed_replacement_terms:
    - id: GO:0004860
      label: protein kinase inhibitor activity
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer placing SOCS1 in cytokine-mediated signaling. Correct
      but general; SOCS1's specific role is negative regulation of JAK-STAT signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but high-level; superseded by the specific negative-regulation term.
- term:
    id: GO:0046426
    label: negative regulation of receptor signaling pathway via JAK-STAT
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of the core JAK-STAT negative-regulation function.
      Fully consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      Core SOCS1 function, corroborated experimentally and by orthology.
- term:
    id: GO:0046627
    label: negative regulation of insulin receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer (mouse O35716) of negative regulation of insulin
      receptor signaling. SOCS1 is reported to attenuate insulin/IGF signaling (e.g. via
      IRS targeting), but this is a secondary, context-specific role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible secondary role; non-core relative to cytokine/JAK regulation.
- term:
    id: GO:0005159
    label: insulin-like growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:9727029
  qualifier: enables
  review:
    summary: >-
      IPI annotation supported by the explicit statement that hSOCS-1 interacts strongly
      with IGF-IR in the two-hybrid assay. Real SH2-mediated interaction, but peripheral
      to SOCS1's canonical cytokine-signaling role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported interaction (PMID:9727029) but a secondary,
      receptor-specific binding rather than a core function.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:9727029
  qualifier: enables
  review:
    summary: >-
      Protein kinase binding annotation (WITH JAK2/O60674). SOCS1 binding to activated
      JAKs through its SH2 domain is central to its mechanism; protein kinase binding is
      an informative, accurate molecular function.
    action: ACCEPT
    reason: >-
      Captures SOCS1's mechanistically essential binding to JAK kinases; core function.
- term:
    id: GO:0046426
    label: negative regulation of receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:9727029
  qualifier: involved_in
  review:
    summary: >-
      Non-traceable author statement of the core JAK-STAT negative-regulation function.
      Consistent with the wealth of experimental evidence even though the assertion here
      is by analogy in a SOCS-2-focused paper.
    action: ACCEPT
    reason: >-
      Core function; abundantly supported elsewhere (PMID:9202125, PMID:9202126).
- term:
    id: GO:0004860
    label: protein kinase inhibitor activity
  evidence_type: TAS
  original_reference_id: PMID:9202125
  qualifier: enables
  review:
    summary: >-
      Traceable-author-statement annotation of protein kinase inhibitor activity from the
      founding SOCS family paper. This is the precise, experimentally grounded core
      molecular function of SOCS1 (direct inhibition of JAK catalytic activity).
    action: ACCEPT
    reason: >-
      Core molecular function; directly supported by PMID:9202125 and PMID:9202126.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9202126
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization from the founding JAB paper. SOCS1 acts on cytoplasmic
      receptor-associated JAKs; cytoplasm/cytosol is its principal compartment.
    action: ACCEPT
    reason: >-
      Primary functional compartment; consistent with cytosol annotations.
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the full repertoire of physiological SOCS1 ubiquitination substrates beyond
    JAKs (e.g. NF-kB RelA, IRS1/2, FAK), and which are degraded versus
    non-degradatively regulated in primary immune cells?
- question: >-
    How is the balance between SOCS1's direct kinase-inhibitory (KIR/SH2) activity and
    its SOCS-box E3-adaptor activity tuned in different cytokine contexts?
suggested_experiments:
- description: >-
    Separation-of-function mutants (KIR-dead vs SOCS-box-dead vs SH2-dead) expressed in
    SOCS1-null cells, with quantitative phospho-JAK/STAT and substrate-degradation
    readouts across IFN-gamma, IL2, IL4 and IL6 stimulation, to dissect the relative
    contributions of kinase inhibition and ubiquitin-mediated degradation.
- description: >-
    Proximity-labeling (BioID/TurboID) and ubiquitin-remnant proteomics in cytokine-
    stimulated primary T cells/macrophages to define the endogenous SOCS1 interactome and
    its degradation targets in a physiological setting.