SOS2 (human, UniProt Q07890) - curation notes
Identity
- UniProt Q07890 (SOS2_HUMAN), 1332 aa, Son of sevenless homolog 2; paralog of SOS1
[file:human/SOS2/SOS2-uniprot.txt].
- Domains: N-terminal histone fold, DH (198-388), PH (442-546), N-terminal Ras-GEF/REM (595-739),
Ras-GEF/CDC25 (778-1017), C-terminal disordered proline-rich region (1142-1332)
[file:human/SOS2/SOS2-uniprot.txt].
- PANTHER PTHR23113 (GUANINE NUCLEOTIDE EXCHANGE FACTOR), subfamily PTHR23113:SF150 (SON OF SEVENLESS
HOMOLOG 2) [file:human/SOS2/SOS2-uniprot.txt]; PAINT node PTN000560991 carries GEF activity and Ras
protein signal transduction (also used in modules/erk_cascade.yaml).
- No GO-CAM model in
gocams/index.tsv contains Q07890.
Molecular function
- Ras GEF [file:human/SOS2/SOS2-uniprot.txt "Acts as guanine nucleotide exchange factor (GEF) for RAS
proteins."]; the CDC25-homology domain promotes GDP release from RAS
[file:human/SOS2/SOS2-deep-research-falcon.md "The CDC25-homology domain destabilizes nucleotide
coordination and promotes GDP dissociation."].
- Cellular evidence: SOS2 in a TPR1-Galpha16 complex enhances Ras activation PMID:20639119.
- Rac/Rho GEF activity of SOS2 (via DH domain) is not established, unlike SOS1
[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."]. The two Reactome cytosol rows come from Rho/Rac GEF events;
the location is fine but the implied activity is provisional.
Recruitment / binding
- GRB2 binds the SOS2 proline-rich C-terminus through its SH3 domains, with higher affinity than SOS1
[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."; "the apparent binding affinity of hSos2 for
Grb2 is significantly higher relative to that of hSos1 both in vitro and in vivo"].
- Other IPI partners are all SH3-domain proteins (NCK1, CRK, PLCG1, ABL1, PACSIN3, SNX9), identified in
SH3/proline-peptide screens [PMID:17474147; PMID:14679214 "The proline-rich Sos peptide retrieved only
SH3 domain containing proteins as specific binding partners."]. All GO:0005515 rows -> MODIFY to
GO:0017124 SH3 domain binding.
Localization
- Cytosolic at rest, acts at the plasma membrane on prenylated RAS after GRB2-mediated recruitment
[file:human/SOS2/SOS2-deep-research-falcon.md "SOS2 is a soluble intracellular protein that is primarily
cytosolic in unstimulated cells."].
Processes
- Ras protein signal transduction (core), downstream of RTKs; contributes preferentially to PI3K-AKT output
in some contexts; partially redundant with SOS1 (Sos2-null mice viable).
- Insulin receptor signalling (IEA from mouse ortholog): plausible, non-core.
Disease
- Noonan syndrome 9 (heterozygous gain-of-function variants) PMID:25795793.
Annotation decisions
- GEF activity (IBA, IEA) ACCEPT; GO:0005085 is the current term (Ras-specific GEF term GO:0005088 no longer
resolves in the GO build).
- GO:0046982 protein heterodimerization activity (InterPro2GO from histone-fold IPR009072) -> REMOVE: the
SOS histone fold is an intramolecular tandem histone-like domain within a single chain, not evidence of a
heterodimerization activity with another protein.
- PMID:19593445 (known batch miscitation) is not present in the SOS2 GOA set.
Earlier independent review on main (commit fda391d9a)
SOS2 was reviewed independently on main (commit fda391d9a) while this review was in progress. When PR #3381 was merged with main (2026-10-08), this review was kept as canonical because it is COMPLETE and re-types bare protein-binding rows to informative terms where the other review removed them; what the other review added that this one lacked was ported: the NEW EGFR signaling pathway row from PMID:30181243 and two open questions. Its notes are preserved below for provenance; its deep-research file is in git history at fda391d9a.
SOS2 (human, Q07890) curation notes
2026-09-30 initial review
Context: reviewed as the SOS2 paralog variant of the Ras GEF step in the FGFR signaling module
(modules/fgfr_signaling.yaml, not edited). SOS1 review (genes/human/SOS1/) used as comparator.
Molecular function: RAS GEF
- GEF activity is SOS2-specific, not only inferred from SOS1. A GEF-dead mutant fails to rescue:
PMID:30181243
- Noonan syndrome DH-domain mutants raise RAS-GTP at near-endogenous expression:
PMID:26173643
- GPCR input: PMID:20639119
- GO:0005088 (Ras GEF activity) no longer resolves in the current GO build (runoak returns None), so GO:0005085 is kept, as for SOS1.
GRB2 / SH3 coupling
- PMID:7629138
- Higher GRB2 affinity than SOS1: PMID:7629138
- The protein binding IPI rows from domain-mapped studies (PMID:7629138, PMID:14679214 SOS proline-rich peptide pull-down, PMID:17474147 SH3 peptide array) -> MODIFY to GO:0017124 SH3 domain binding. The high-throughput AP-MS/Y2H rows -> REMOVE (uninformative), matching SOS1.
SOS2 vs SOS1 (redundancy)
Decisions
- GEF (IBA, IEA), Ras protein signal transduction (IBA), small GTPase-mediated signal transduction (IEA), plasma membrane (IBA), cytosol (IEA, 2x Reactome TAS): ACCEPT. Reactome rows are RHO/RAC-activation reactions whose SOS2 involvement is weak, but the location is right.
- Insulin receptor signaling (IEA Ensembl Compara): KEEP_AS_NON_CORE (generic RTK-GRB2-SOS step; no SOS2-specific evidence).
- Protein heterodimerization activity (IEA, histone-fold InterPro2GO): REMOVE (domain mapping artifact; also removed for SOS1).
- NEW: GO:0007173 EGFR signaling pathway, IMP PMID:30181243. Participation: SOS2 performs the GEF step. Comparator: SOS1 carries the term.
- No FGFR-specific SOS2 evidence found; FGFR role is inferred from the shared GRB2 mechanism (raised as a question, not annotated).