SOCS5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0019221 cytokine-mediated signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: SOCS5 is a well-established negative regulator of cytokine signaling, particularly IL-4 and IL-6 pathways. This IBA annotation is phylogenetically sound and represents a core function of SOCS5. Reason: This annotation accurately represents a core function of SOCS5. UniProt states "SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction" and specifically notes involvement in IL-4, IL-6, and LIF signaling pathways. IBA evidence provides strong phylogenetic support for this conserved function across SOCS family members. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. [...] Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype. Can also partially inhibit IL6 and LIF signaling. file:human/SOCS5/SOCS5-deep-research-openai.md See deep research file for comprehensive analysis
GO:0007173 epidermal growth factor receptor signaling pathway	IEA GO_REF:0000120	ACCEPT	Summary: SOCS5 negatively regulates EGFR signaling by promoting EGFR degradation. This is a well-documented function supported by experimental evidence. Reason: This annotation is supported by direct experimental evidence showing SOCS5 regulates EGFR signaling. PMID:15590694 demonstrates that SOCS5 expression leads to marked reduction in EGFR levels by promoting degradation, and that this requires both the SH2 and SOCS box domains. The IEA evidence code is conservative given the strong experimental support available. Supporting Evidence: PMID:15590694 The expression of SOCS5 led to a marked reduction in EGFR expression levels by promoting EGFR degradation. [...] SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IEA GO_REF:0000002	ACCEPT	Summary: SOCS5 is a negative regulator of JAK-STAT signaling, which is the canonical mechanism for SOCS family proteins. This represents a core molecular function. Reason: SOCS proteins are classical negative regulators of JAK-STAT signaling pathways. PMID:10773671 describes SOCS5 (CIS6) as structurally related to other CIS family members that act as negative regulators of JAK signaling. The protein is named "Suppressor of cytokine signaling" precisely because it inhibits this pathway. This annotation accurately captures core function. Supporting Evidence: PMID:10773671 A family of negative regulators of JAK signaling pathway referred to as suppressor of cytokines signaling (SOCS) or cytokine-inducible SH2 protein (CIS) has been recently identified. [...] CIS6 is structurally related to other members of the CIS family and therefore could act as a negative regulator of signal transduction.
GO:0009968 negative regulation of signal transduction	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: While accurate, this term is too general. SOCS5 specifically regulates cytokine and growth factor receptor signaling pathways, captured by more specific child terms already annotated. Reason: This is a very broad parent term that is technically correct but not informative. SOCS5 function is better captured by more specific terms like "cytokine-mediated signaling pathway" (GO:0019221), "JAK-STAT pathway" (GO:0007259), and "EGFR signaling pathway" (GO:0007173). This represents over-annotation with an overly general term that adds little value beyond the specific annotations. More specific term like "negative regulation of immune response" (GO:0050777) would be more informative given SOCS5 role in Th1/Th2 differentiation.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000002	ACCEPT	Summary: SOCS5 functions as part of an E3 ubiquitin ligase complex and promotes proteasomal degradation of target proteins including EGFR. This is a core molecular mechanism of SOCS5 function. Reason: This annotation accurately captures the mechanism by which SOCS5 exerts its regulatory effects. SOCS5 contains a SOCS box domain that mediates interaction with Elongin BC complex, an adapter in E3 ubiquitin ligase complexes. PMID:15590694 demonstrates that SOCS5 promotes EGFR ubiquitination and degradation via this mechanism. This is a fundamental aspect of SOCS5 function. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. [...] The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes. PMID:15590694 SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation
GO:0035556 intracellular signal transduction	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: This is a very broad parent term that is technically correct but provides limited information. SOCS5 function is better captured by more specific regulatory terms. Reason: This term is overly general and does not add informative value beyond the more specific annotations already present. SOCS5 is involved in intracellular signal transduction, but this is better captured by specific terms like "cytokine-mediated signaling pathway", "JAK-STAT pathway", and "EGFR signaling pathway" that describe the actual pathways regulated. This represents annotation to a high-level parent term that is not informative.
GO:0005515 protein binding	IPI PMID:24728074 Enhanced prediction of Src homology 2 (SH2) domain binding p...	MODIFY	Summary: Generic protein binding term is not informative. SOCS5 has specific binding activities that should be annotated with more specific molecular function terms. Reason: Per curation guidelines, "protein binding" is not informative and should be replaced with more specific molecular function terms. SOCS5 has well-characterized specific binding activities including receptor tyrosine kinase binding (EGFR) and IL-4 receptor binding. These specific functions are already captured by other annotations like GO:0030971 (receptor tyrosine kinase binding). Proposed replacements: receptor tyrosine kinase binding protein kinase inhibitor activity Supporting Evidence: PMID:24728074 Epub 2014 Apr 12. Enhanced prediction of Src homology 2 (SH2) domain binding potentials using a fluorescence polarization-derived c-Met, c-Kit, ErbB, and androgen receptor interactome.
GO:0005154 epidermal growth factor receptor binding	IEA GO_REF:0000107	ACCEPT	Summary: SOCS5 directly binds to EGFR, which is essential for its function in promoting EGFR degradation. This specific molecular function is well-supported. Reason: This annotation accurately captures a specific molecular function of SOCS5. PMID:15590694 demonstrates that SOCS5 can associate with EGFR through its SH2 domain, and this interaction is required for SOCS5 to mediate EGFR degradation. This is more informative than the generic "protein binding" term. Supporting Evidence: PMID:15590694 SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation. file:human/SOCS5/SOCS5-uniprot.txt Interacts with EGFR. Interacts with ELOB and ELOC; mediates EGFR ubiquitination and degradation.
GO:0019221 cytokine-mediated signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate annotation of GO:0019221, already annotated with IBA evidence. The IBA annotation should be retained as it has stronger phylogenetic support. Reason: This is a duplicate of the earlier GO:0019221 annotation with IBA evidence. Both annotations are correct and can coexist with different evidence codes, showing convergent support from both phylogenetic inference (IBA) and orthology-based transfer (IEA via Ensembl Compara). The annotation is valid and represents core function.
GO:0032715 negative regulation of interleukin-6 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SOCS5 can partially inhibit IL-6 signaling according to UniProt, supporting this annotation. However, this appears to be a secondary function compared to IL-4 regulation. Reason: UniProt states that SOCS5 "can also partially inhibit IL6 and LIF signaling" but the primary cytokine target appears to be IL-4. The term "negative regulation of interleukin-6 production" is more specific than needed - SOCS5 inhibits IL-6 signaling rather than production per se. This is a valid but peripheral function, not core to SOCS5 biology. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype. Can also partially inhibit IL6 and LIF signaling.
GO:0045627 positive regulation of T-helper 1 cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: SOCS5 promotes Th1 differentiation indirectly by inhibiting IL-4 signaling, which normally drives Th2 differentiation. This is a well-supported immunological function. Reason: This annotation captures an important immunological role of SOCS5. By inhibiting IL-4 signaling (which promotes Th2 differentiation), SOCS5 shifts the balance toward Th1 differentiation. This is a key function in regulating T-helper cell fate and represents a core biological role of SOCS5 in adaptive immunity. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype.
GO:0045629 negative regulation of T-helper 2 cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: SOCS5 inhibits Th2 differentiation by blocking IL-4 signaling pathway. This is the direct mechanism underlying SOCS5 role in T-helper cell regulation. Reason: This annotation directly describes the mechanistic basis of SOCS5 function in T-cell biology. IL-4 signaling promotes Th2 differentiation, and SOCS5 inhibits this pathway, thereby preventing Th2 differentiation. This is explicitly stated in UniProt and represents a core immunological function of SOCS5. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype.
GO:0050728 negative regulation of inflammatory response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SOCS5 role in regulating inflammatory response is inferred from its regulation of cytokine signaling and T-cell differentiation, but direct evidence for anti-inflammatory function is limited. Reason: While SOCS5 regulates cytokine signaling pathways involved in inflammation, this annotation represents an indirect or downstream consequence rather than a direct core function. The regulation of Th1/Th2 balance and cytokine signaling may influence inflammatory responses, but this is not the primary or direct function of SOCS5. This is a reasonable inference but peripheral to core SOCS5 biology.
GO:0071404 cellular response to low-density lipoprotein particle stimulus	IEA GO_REF:0000107	UNDECIDED	Summary: This annotation appears to be based on orthology transfer but lacks direct experimental support for human SOCS5. The connection to LDL response is not evident in primary literature. Reason: This is a highly specific annotation that does not appear in the UniProt entry or primary publications for human SOCS5. While transferred via Ensembl Compara orthology, there is no clear mechanistic link between SOCS5 core functions (cytokine signaling regulation, EGFR degradation) and LDL particle response. This may represent species-specific function or context-dependent regulation that requires additional literature review to validate.
GO:0071638 negative regulation of monocyte chemotactic protein-1 production	IEA GO_REF:0000107	UNDECIDED	Summary: This highly specific annotation lacks direct experimental support in available literature for human SOCS5. MCP-1 regulation may be downstream of cytokine signaling but is not a documented core function. Reason: This annotation is very specific and does not appear in UniProt or primary publications for human SOCS5. While MCP-1/CCL2 is involved in inflammation and could theoretically be regulated downstream of cytokine pathways that SOCS5 affects, there is no direct evidence in the available literature supporting this specific function. Requires additional literature review to validate or remove.
GO:0097699 vascular endothelial cell response to fluid shear stress	IEA GO_REF:0000107	UNDECIDED	Summary: This highly specific cell type and stimulus annotation lacks supporting evidence in available literature. No clear connection to core SOCS5 functions. Reason: This is a very specific annotation involving endothelial cells and mechanical stimuli that does not appear in UniProt or primary publications for SOCS5. There is no obvious mechanistic connection between SOCS5 core functions (cytokine/growth factor receptor regulation) and response to shear stress in endothelial cells. This may be based on high-throughput data or indirect orthology transfer. Requires additional literature review to validate.
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: SOCS5 is involved in protein ubiquitination as a substrate recognition component of E3 ligase complexes. This is accurate but more specific regulatory term (GO:0032436) is already annotated. Reason: This annotation is correct - SOCS5 functions as part of an E3 ubiquitin ligase complex to promote ubiquitination of target proteins like EGFR. However, the more specific term "positive regulation of proteasomal ubiquitin-dependent protein catabolic process" (GO:0032436) better captures the regulatory nature of this function. Both annotations can coexist as they describe different aspects of the same mechanism. Supporting Evidence: file:human/SOCS5/SOCS5-uniprot.txt May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	NEW	Summary: SOCS5 acts as a substrate-recognition adaptor for an Elongin BC-CUL2/5-SOCS-box E3 ubiquitin ligase complex that targets EGFR and related signaling proteins for ubiquitination-dependent downregulation. Reason: This is the same molecular-function boundary used for KCTD11 and SOCS4. SOCS5 is not the catalytic ubiquitin-transfer subunit; its specific role is substrate recognition plus recruitment of the ligase scaffold, which is captured by GO:1990756. Supporting Evidence: PMID:15590694 SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation. file:human/SOCS5/SOCS5-uniprot.txt May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
GO:0005829 cytosol	TAS Reactome:R-HSA-6785821	ACCEPT	Summary: SOCS5 localizes to the cytosol where it functions in regulating cytokine and growth factor receptor signaling. Multiple Reactome pathways support cytosolic localization. Reason: Cytosolic localization is consistent with SOCS5 function as an intracellular regulator of receptor signaling. SOCS5 must be in the cytosol to interact with cytoplasmic portions of receptors and E3 ligase components. Reactome pathway R-HSA-6785821 describes SOCS5 binding to IL4RA in the cytosol, supporting this localization. Supporting Evidence: Reactome:R-HSA-6785821 SOCS5,(SOCS1) bind IL4RA
GO:0005829 cytosol	TAS Reactome:R-HSA-8952039	ACCEPT	Summary: Duplicate cytosol annotation based on different Reactome pathway (neddylation of CRL5 complex). Supports same localization. Reason: This is a duplicate localization annotation based on SOCS5 participation in CRL5 E3 ubiquitin ligase complex neddylation, which occurs in the cytosol. Consistent with core SOCS5 function as part of E3 ligase machinery.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952044	ACCEPT	Summary: Duplicate cytosol annotation based on neddylation pathway. Supports same localization. Reason: Another duplicate based on Reactome neddylation pathway showing SOCS5-containing CRL5 complex in cytosol. Consistent with E3 ligase function.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	ACCEPT	Summary: Duplicate cytosol annotation. All Reactome pathways consistently place SOCS5 in cytosol. Reason: Duplicate annotation based on CAND1 binding to CRL complexes in cytosol. Consistent localization across multiple pathways.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	ACCEPT	Summary: Duplicate cytosol annotation from Reactome pathway. Reason: Duplicate annotation based on COMMD protein regulation of CRL complexes in cytosol. Consistent localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	ACCEPT	Summary: Duplicate cytosol annotation from Reactome deneddylation pathway. Reason: Duplicate annotation based on COP9 signalosome deneddylation of CRL complexes in cytosol. Consistent with other pathways.
GO:0005515 protein binding	IPI PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	MODIFY	Summary: Duplicate of earlier protein binding annotation, same issues apply. Not informative, should be replaced with specific binding terms. Reason: This is a second instance of the generic "protein binding" annotation, this time with IPI evidence from PMID:15590694. As noted in the previous protein binding review, this term is not informative per curation guidelines. The specific binding partners and functions are better captured by terms like receptor tyrosine kinase binding (GO:0030971) and EGFR binding (GO:0005154). Proposed replacements: receptor tyrosine kinase binding protein-containing complex binding Supporting Evidence: PMID:15590694 2004 Dec 7. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling.
GO:0007175 negative regulation of epidermal growth factor-activated receptor activity	IDA PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	ACCEPT	Summary: SOCS5 directly inhibits EGFR activity by promoting its degradation, demonstrated by IDA evidence. This is a core molecular function of SOCS5. Reason: This annotation has strong experimental support (IDA) from PMID:15590694, which demonstrates that SOCS5 expression reduces EGFR levels and suppresses EGF-induced signaling. This represents the specific regulatory function of SOCS5 on EGFR activity and is a well-characterized core function. The experimental evidence directly supports this annotation. Supporting Evidence: PMID:15590694 The expression of SOCS5 led to a marked reduction in EGFR expression levels by promoting EGFR degradation. The reduction in EGFR levels and EGF-induced signaling in SOCS5-expressing cells requires both the Src homology-2 and SOCS box domains of SOCS5.
GO:0030971 receptor tyrosine kinase binding	IPI PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	ACCEPT	Summary: SOCS5 binds to receptor tyrosine kinases, specifically EGFR, through its SH2 domain. This is a key molecular function with strong experimental support. Reason: This annotation accurately captures a specific molecular function of SOCS5 with IPI evidence. PMID:15590694 demonstrates protein-protein interaction between SOCS5 and EGFR (a receptor tyrosine kinase). This is far more informative than the generic "protein binding" term and represents a core molecular function required for SOCS5 to regulate EGFR signaling. Supporting Evidence: PMID:15590694 SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation file:human/SOCS5/SOCS5-uniprot.txt Interacts with EGFR.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:15590694 Suppressors of cytokine signaling 4 and 5 regulate epidermal...	ACCEPT	Summary: Duplicate of earlier GO:0032436 annotation, this time with IMP evidence. Both annotations are valid and represent core SOCS5 function. Reason: This is a duplicate annotation with mutant phenotype evidence (IMP) from PMID:15590694. The study shows that mutants in SOCS5 SH2 domain or SOCS box abrogate the ability to promote EGFR degradation, providing strong genetic evidence for this function. Both IEA and IMP annotations can coexist, with the IMP providing stronger experimental support for this core regulatory mechanism. Supporting Evidence: PMID:15590694 The reduction in EGFR levels and EGF-induced signaling in SOCS5-expressing cells requires both the Src homology-2 and SOCS box domains of SOCS5. [...] SOCS5 can associate with EGFR and can also bind the ElonginBC protein complex via its SOCS box, which may recruit an E3 ubiquitin ligase to promote EGFR degradation.
GO:0019221 cytokine-mediated signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Third instance of GO:0019221 annotation, this time with ISS (sequence similarity) evidence. Convergent support for core function. Reason: This is a third annotation of the same term with ISS evidence based on manual transfer to orthologs. The convergence of IBA, IEA, and ISS evidence all supporting the same annotation strengthens confidence that cytokine-mediated signaling is a core conserved function of SOCS5 across species.
GO:0045627 positive regulation of T-helper 1 cell differentiation	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of earlier Th1 differentiation annotation, this time with ISS evidence from orthology. Reason: This is a duplicate annotation with ISS evidence based on manual orthology transfer. Both IEA and ISS annotations supporting the same function provide convergent evidence for this conserved immunological role across species.
GO:0045629 negative regulation of T-helper 2 cell differentiation	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate of earlier Th2 differentiation annotation with ISS evidence. Reason: Duplicate annotation with ISS evidence from orthology transfer. Convergent with IEA annotation, supporting conserved function in regulating T-helper cell fate.
GO:0009968 negative regulation of signal transduction	NAS PMID:10773671 Cloning and expression of CIS6, chromosome assignment to 3p2...	MARK AS OVER ANNOTATED	Summary: Fourth instance of this overly broad term, this time with NAS evidence from the original SOCS5 cloning paper. Same issues as earlier instances. Reason: This is another instance of the overly general "negative regulation of signal transduction" term, this time with NAS evidence from PMID:10773671 (the original cloning paper describing SOCS5/CIS6). While the statement in that paper that SOCS5 could act as a negative regulator is accurate, this broad term is not informative compared to the specific pathway annotations already present. Supporting Evidence: PMID:10773671 Cloning and expression of CIS6, chromosome assignment to 3p22 and 2p21 by in situ hybridization.

Gene Description

Existing Annotations Review

Core Functions

substrate recognition component of E3 ubiquitin ligase complex targeting EGFR for proteasomal degradation

negative regulation of IL-4 receptor signaling via JAK-STAT pathway

References

Deep Research

Cyberian

Falcon

OpenAI

📚 Additional Documentation

Review Summary

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