Son of sevenless homolog 2 (SOS2) is a large cytosolic Ras guanine nucleotide exchange factor (RasGEF), the paralog of SOS1. It comprises an N-terminal tandem histone-fold region, a Dbl-homology (DH) and pleckstrin-homology (PH) regulatory unit, a catalytic core of Ras exchanger motif (REM) and CDC25-homology domains, and a C-terminal proline-rich tail. In resting cells SOS2 is cytosolic and autoinhibited; after receptor tyrosine kinase activation the SH3 domains of the adaptor GRB2 bind the SOS2 proline-rich tail (with higher affinity than for SOS1) and recruit it to phosphotyrosine sites at the plasma membrane, where the CDC25 domain catalyses GDP release from HRAS, KRAS and NRAS, allowing GTP loading and activation of RAF-MEK-ERK and PI3K-AKT signalling. SOS2 is partly redundant with SOS1 (Sos2-null mice are viable) but contributes preferentially to RTK-driven PI3K-AKT signalling in some cell types, to epidermal stem-cell maintenance and to the anchorage-independent survival of KRAS-mutant cancer cells. Heterozygous activating SOS2 variants in the DH region cause Noonan syndrome 9.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA guanyl-nucleotide exchange factor activity from PAINT node PTN000560991 (PTHR23113 RasGEF family), whose experimental donors span RasGEF family members from yeast, Dictyostelium, worm and fly to mammals, including human SOS1. Reason: Core molecular function. SOS2 has an intact REM plus CDC25-homology catalytic module and promotes GDP-to-GTP exchange on RAS; SOS2 lies within the clade to which PAINT assigned the activity, with no evidence of loss. Supporting Evidence: file:human/SOS2/SOS2-uniprot.txt Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. file:human/SOS2/SOS2-deep-research-falcon.md The CDC25-homology domain destabilizes nucleotide coordination and promotes GDP dissociation. PMID:20639119 Expression of SOS2 enhanced Galpha16QL-induced Ras activation and its subsequent signaling. PMID:26173643 SOS2 stimulates the release of GDP from RAS, promoting the conversion of the GTPase from the inactive, GDP-bound to the active, GTP-bound form PMID:26173643 These findings are consistent with a direct GOF effect on the RAS-GEF activity of NS-associated SOS2 mutations. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA guanyl-nucleotide exchange factor activity from combined InterPro (RasGEF/DH domains) and ortholog evidence (GO_REF:0000120). Reason: Correct; duplicate of the IBA core MF. Supporting Evidence: file:human/SOS2/SOS2-uniprot.txt Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. PMID:26173643 SOS2 stimulates the release of GDP from RAS, promoting the conversion of the GTPase from the inactive, GDP-bound to the active, GTP-bound form |
| GO:0005515 protein binding | IPI PMID:14679214 A novel proteomic screen for peptide-protein interactions. | MODIFY | Summary: IPI for SOS2 binding GRB2, from a SILAC peptide pull-down screen in which a SOS proline-rich peptide retrieved only SH3-domain proteins. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:14679214 The proline-rich Sos peptide retrieved only SH3 domain containing proteins as specific binding partners. PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:14679214 A novel proteomic screen for peptide-protein interactions. | MODIFY | Summary: IPI for SOS2 binding PACSIN3, from a SILAC peptide pull-down screen in which a SOS proline-rich peptide retrieved only SH3-domain proteins. PACSIN3 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:14679214 The proline-rich Sos peptide retrieved only SH3 domain containing proteins as specific binding partners. |
| GO:0005515 protein binding | IPI PMID:14679214 A novel proteomic screen for peptide-protein interactions. | MODIFY | Summary: IPI for SOS2 binding SNX9, from a SILAC peptide pull-down screen in which a SOS proline-rich peptide retrieved only SH3-domain proteins. SNX9 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:14679214 The proline-rich Sos peptide retrieved only SH3 domain containing proteins as specific binding partners. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MODIFY | Summary: IPI for SOS2 binding ABL1, from a peptide-array screen of SH3 domains (SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) against proline-rich ligands. ABL1 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MODIFY | Summary: IPI for SOS2 binding NCK1, from a peptide-array screen of SH3 domains (SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) against proline-rich ligands. NCK1 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MODIFY | Summary: IPI for SOS2 binding PLCG1, from a peptide-array screen of SH3 domains (SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) against proline-rich ligands. PLCG1 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MODIFY | Summary: IPI for SOS2 binding CRK, from a peptide-array screen of SH3 domains (SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) against proline-rich ligands. CRK is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | MODIFY | Summary: IPI for SOS2 binding GRB2, from a peptide-array screen of SH3 domains (SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) against proline-rich ligands. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:19380743 Charting the molecular network of the drug target Bcr-Abl. | MODIFY | Summary: IPI for SOS2 binding CRK, from TAP/MS charting of the Bcr-Abl interaction network, whose core components include Grb2 and Crk-I. CRK is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MODIFY | Summary: IPI for SOS2 binding GRB2, from a large-scale human MAP kinase interactome. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:21706016 Selected reaction monitoring mass spectrometry reveals the d... | MODIFY | Summary: IPI for SOS2 binding GRB2, from AP-SRM quantification of GRB2 complexes after growth-factor stimulation. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MODIFY | Summary: IPI for SOS2 binding GRB2, from a human liver proteome-scale yeast two-hybrid network. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: IPI for SOS2 binding GRB2, from the BioPlex 2.0 AP-MS interactome. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: IPI for SOS2 binding GRB2, from AP-MS rewiring analysis of the EGFR network in KRAS(G13D) colorectal cancer cells. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI for SOS2 binding NCK1, from the BioPlex 3.0 AP-MS interactome. NCK1 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI for SOS2 binding CRK, from the BioPlex 3.0 AP-MS interactome. CRK is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI for SOS2 binding GRB2, from the BioPlex 3.0 AP-MS interactome. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: IPI for SOS2 binding NCK1, from multimodal (AP-MS plus imaging) human cell maps. NCK1 is an SH3-domain protein, and SOS proteins engage SH3 domains through their C-terminal proline-rich region. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: IPI for SOS2 binding GRB2, from multimodal (AP-MS plus imaging) human cell maps. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005515 protein binding | IPI PMID:7629138 Differential interactions of human Sos1 and Sos2 with Grb2. | MODIFY | Summary: IPI for SOS2 binding GRB2, from a focused comparison of human Sos1 and Sos2 binding to Grb2. GRB2 recruits SOS2 to activated receptors by binding the SOS2 C-terminal proline-rich region with its SH3 domains (the defining SOS-GRB2 coupling); SOS2 binds GRB2 with higher affinity than SOS1. Reason: GO:0005515 'protein binding' is uninformative. The partner binds via its SH3 domain(s) to the SOS2 proline-rich tail, so GO:0017124 SH3 domain binding captures the molecular basis of the interaction and the adaptor-mediated recruitment of SOS2 to receptors. Deferring to the curator on the interaction itself. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:7629138 We show that hSos2 interacts with Grb2 via its proline-rich COOH-terminal domain and that this interaction is dependent on the SH3 domains of Grb2. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: IEA cytosol from an ARBA machine-learning rule. Reason: SOS2 is cytosolic in unstimulated cells before GRB2-mediated recruitment to membranes. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md SOS2 is a soluble intracellular protein that is primarily cytosolic in unstimulated cells. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-205039 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-205039, a Rho-family (RAC/Cdc42 or RhoA/B/C) GEF activation event in which SOS2 is listed among candidate GEFs. Reason: The cytosolic location of SOS2 is correct. Note that the Rho/Rac GEF activity implied by these Reactome events is provisional for SOS2 (demonstrated for SOS1 but not formally for SOS2); that caveat does not affect the location annotation. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md SOS2 is a soluble intracellular protein that is primarily cytosolic in unstimulated cells. file:human/SOS2/SOS2-deep-research-falcon.md SOS1 is a demonstrated RAC-GEF, whereas SOS2 has supporting interaction and homology evidence but had not, as of the authoritative 2021 synthesis, been formally established as an equivalent RAC-GEF. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-419166 | ACCEPT | Summary: TAS cytosol from Reactome event Reactome:R-HSA-419166, a Rho-family (RAC/Cdc42 or RhoA/B/C) GEF activation event in which SOS2 is listed among candidate GEFs. Reason: The cytosolic location of SOS2 is correct. Note that the Rho/Rac GEF activity implied by these Reactome events is provisional for SOS2 (demonstrated for SOS1 but not formally for SOS2); that caveat does not affect the location annotation. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md SOS2 is a soluble intracellular protein that is primarily cytosolic in unstimulated cells. file:human/SOS2/SOS2-deep-research-falcon.md SOS1 is a demonstrated RAC-GEF, whereas SOS2 has supporting interaction and homology evidence but had not, as of the authoritative 2021 synthesis, been formally established as an equivalent RAC-GEF. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA plasma membrane (is_active_in) from PTHR23113 SOS clade. Reason: SOS2 exerts its GEF activity at the cytoplasmic face of the plasma membrane, where prenylated RAS resides, after GRB2-mediated recruitment to activated receptors. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md GRB2 binds the receptor directly or through adaptors such as SHC and uses its SH3 domains to engage the proline-rich SOS2 tail, increasing the local concentration of SOS2 near membrane-bound RAS. |
| GO:0007264 small GTPase-mediated signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA small GTPase-mediated signal transduction from RasGEF InterPro signatures. Reason: Correct but general parent of GO:0007265 Ras protein signal transduction, which is accepted from IBA. Supporting Evidence: file:human/SOS2/SOS2-uniprot.txt Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. |
| GO:0007265 Ras protein signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA Ras protein signal transduction from PAINT node PTN000560991 (SOS clade), shared with SOS1. Reason: Core process: SOS2 converts RAS-GDP to RAS-GTP downstream of receptor tyrosine kinases, feeding RAF-MEK-ERK and PI3K-AKT outputs. Supporting Evidence: file:human/SOS2/SOS2-uniprot.txt Acts as guanine nucleotide exchange factor (GEF) for RAS proteins. PMID:20639119 Expression of SOS2 enhanced Galpha16QL-induced Ras activation and its subsequent signaling. |
| GO:0008286 insulin receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA insulin receptor signaling pathway transferred from the mouse ortholog via Ensembl Compara. Reason: Plausible: GRB2-SOS couples insulin/IGF receptor substrates to RAS. It is one of several RTK contexts in which SOS2 acts rather than a defining function, so non-core. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md GRB2 binds the receptor directly or through adaptors such as SHC and uses its SH3 domains to engage the proline-rich SOS2 tail, increasing the local concentration of SOS2 near membrane-bound RAS. |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000002 | REMOVE | Summary: IEA protein heterodimerization activity from the InterPro histone-fold signature (IPR009072) via InterPro2GO. Reason: The InterPro2GO mapping is appropriate for true histone-fold heterodimers (e.g. H2A/H2B, NF-Y) but not for SOS proteins, whose N-terminal histone-fold region is a tandem pair of histone-like folds within a single polypeptide that contributes to membrane binding and autoinhibition. There is no evidence that SOS2 heterodimerizes with another protein through this domain. Supporting Evidence: file:human/SOS2/SOS2-deep-research-falcon.md N-terminal tandem histone-fold region |
| GO:0007173 epidermal growth factor receptor signaling pathway | IMP PMID:30181243 Oncogenic RAS isoforms show a hierarchical requirement for t... | NEW | Summary: SOS2 performs the RAS-activating step of EGFR signaling: Sos2 deletion reduces EGF-stimulated activation of wild-type HRAS, which is restored by wild-type but not GEF-dead SOS2; SOS2 forms EGF-induced complexes with EGFR and SHC; and SOS2 loss raises the threshold of mutant-EGFR signaling in lung adenocarcinoma cells. Reason: Participation test: SOS2 does part of the work of this pathway (the GEF step that converts RAS-GDP to RAS-GTP downstream of GRB2-bound EGFR), not merely being required for it. Comparator check: the paralog SOS1, which occupies the same role, carries GO:0007173. The evidence is SOS2-specific (rescue with GEF-dead mutant) rather than inferred from SOS1. Supporting Evidence: PMID:30181243 Sos2 deletion reduced epidermal growth factor (EGF)-dependent activation of wild-type HRAS and phosphorylation of the kinase AKT in cells expressing mutant RAS isoforms. PMID:30181243 These data indicate that SOS2 GEF activity, but not allosteric feedback activation of SOS2 by oncogenic KRAS, is key to SOS2-dependent activation of wild-type HRAS downstream of RTKs. PMID:10675333 formed complexes between Sos2, epidermal growth factor receptor (EGFR) and Shc efficiently, gave normal Ras⋅GTP and ERK responses when treated with EGF for ⩽10 min PMID:38073064 Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)-dependent RAS activation. |
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Download this section (compressed HTML)Q: Does SOS2, like SOS1, have genuine Rac GEF activity through its DH-PH unit, which would justify the Reactome Rho/Rac GEF events that currently include SOS2?
Q: Is allosteric activation by RAS-GTP binding at the REM site as important for SOS2 as it is for SOS1, and does it explain the shorter-lived signals attributed to SOS2?
Q: What determines the preferential coupling of SOS2-generated RAS-GTP to PI3K-AKT rather than ERK output in keratinocytes and KRAS-mutant cells?
Q: What structural feature of the divergent SOS2 C-terminal tail (only about 40% identical to SOS1) makes GRB2-SOS2 complexes bind activated EGFR and SHC less stably than GRB2-SOS1, despite higher GRB2 affinity?
Q: Does SOS2 contribute to FGFR signaling through the FRS2-GRB2 docking complex in the same way as SOS1? No SOS2-specific FGFR evidence was found; the role is inferred from the shared GRB2-coupled mechanism.
Experiment: Measure intrinsic and RAS-GTP-stimulated nucleotide exchange of purified full-length and catalytic-domain SOS2 on HRAS, KRAS and NRAS (and on RAC1) side by side with SOS1.
Experiment: Test Noonan syndrome 9 DH-domain variants in reconstituted membrane assays to determine whether they relieve autoinhibition of SOS2 GEF activity.
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