SOS1 Gene - Son of Sevenless Homolog 1
A key RAS guanine nucleotide exchange factor in development and disease
Gene Information Card
| Symbol | SOS1 |
|---|---|
| Full Name | SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 2p22.1 |
| NCBI Gene ID | 6654 ncbi.nlm.nih.gov/gene/6654 |
| Ensembl ID | ENSG00000115904 |
| UniProt ID | Q07889 |
| OMIM ID | 182530 |
| HGNC ID | 11187 |
| Aliases | GF1, GGF1, GINGF1, HGF, NS4 |
Description
SOS1 (SOS Ras/Rac Guanine Nucleotide Exchange Factor 1) encodes a protein that acts as a guanine nucleotide exchange factor (GEF) for RAS and RAC1. It activates the RAS-MAPK signaling pathway by promoting the exchange of GDP for GTP on small GTPases. SOS1 is critical for embryonic development, cell proliferation, and differentiation. Mutations in SOS1 cause Noonan syndrome type 4 and hereditary gingival fibromatosis type 1, and are also implicated in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Noonan syndrome 4 | Gain-of-function mutations in SOS1 lead to increased RAS-MAPK signaling, causing developmental abnormalities including short stature, facial dysmorphism, and cardiac defects. | OMIM #610733; ClinVar |
| Hereditary gingival fibromatosis 1 | Loss-of-function or dominant-negative mutations disrupt normal gingival tissue homeostasis, resulting in overgrowth of gingival tissue. | OMIM #135300; ClinVar |
| Lung cancer | Somatic mutations (e.g., p.E846K, p.R552G) activate SOS1 GEF activity, promoting oncogenic RAS signaling. | COSMIC; PMID: 17344846 |
| Colorectal cancer | Amplification and overexpression of SOS1 contribute to aberrant MAPK pathway activation. | COSMIC; PMID: 23431135 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 14.2 | Medium |
| Lung | 11.8 | Medium |
| Heart | 9.5 | Low |
| Liver | 7.3 | Low |
| Kidney | 12.1 | Medium |
| Testis | 20.5 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 18.3 | High expression |
| HeLa | 15.7 | Medium-high |
| A549 | 12.4 | Medium |
| MCF7 | 10.1 | Medium |
| K562 | 8.9 | Low-medium |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Ser548Arg | Missense | Rare | Gain-of-function; associated with Noonan syndrome |
| p.Glu846Lys | Missense | Somatic (cancer) | Gain-of-function; increases RAS-GTP levels |
| p.Arg552Gly | Missense | Somatic (cancer) | Gain-of-function; enhances GEF activity |
| p.Leu550Pro | Missense | Rare | Loss-of-function; associated with gingival fibromatosis |
Mutation functional classification
Loss of Function (LOF)
Mutations in the PH or DH domains (e.g., p.Leu550Pro) reduce GEF activity, leading to hereditary gingival fibromatosis type 1.
Gain of Function (GOF)
Mutations in the catalytic domain or allosteric regions (e.g., p.Ser548Arg, p.Glu846Lys) increase RAS-GTP exchange, causing Noonan syndrome and promoting oncogenesis.
Dominant Negative (DN)
Some mutations (e.g., p.Arg552Gly) may act in a dominant-negative manner by sequestering RAS or disrupting normal SOS1 dimerization, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
Pathways
• RAS signaling pathway (Reactome: R-HSA-167044)
• MAPK signaling pathway (KEGG: hsa04010)
• Signaling by EGFR (Reactome: R-HSA-177929)
• Signaling by FGFR (Reactome: R-HSA-190236)
• Diseases of signal transduction (Reactome: R-HSA-5663202)
Protein Summary
SOS1 is a 1333-amino acid multidomain protein containing an N-terminal histone-like domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a Ras exchanger motif (REM), and a C-terminal catalytic domain. It functions as a GEF for RAS and RAC1, coupling receptor tyrosine kinase activation to the MAPK cascade. The protein is autoinhibited in its basal state and activated by binding to phosphorylated adaptors such as GRB2. Dysregulation of SOS1 underlies developmental disorders and multiple cancer types.
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