SOS1

SOS1 (Son of sevenless homolog 1) is a large multidomain cytoplasmic guanine-nucleotide exchange factor (GEF) that activates RAS-family small GTPases. Through its central REM-CDC25 (Ras-GEF) module it catalyzes release of GDP from H-, N- and K-RAS, allowing GTP to load and switch RAS into its active signaling state; it does not hydrolyze or transfer nucleotide itself. SOS1 is recruited from the cytosol to the inner face of the plasma membrane downstream of activated receptor tyrosine kinases, where its proline-rich C-terminal tail binds the SH3 domains of the adaptor GRB2 (docked on phosphorylated receptors or SHC), positioning SOS1 next to lipid-anchored RAS. Its activity is tightly regulated: an N-terminal histone-fold/DH-PH region autoinhibits the catalytic module, and this is relieved by membrane lipids and by RAS-GTP binding an allosteric REM-CDC25 site that drives positive feedback. SOS1 thereby acts as a key activating node of the RAS-RAF-MEK-ERK (MAPK) cascade controlling proliferation, differentiation, survival and migration downstream of many growth-factor, cytokine and antigen receptors. In addition to RAS-GEF activity, its Dbl-homology (DH) domain, acting in complexes such as EPS8-ABI1, links RAS signaling to activation of the RHO-family GTPase RAC1 and cytoskeletal/JNK signaling, and SOS1 can act as a scaffold within phase-separated receptor signalosomes. Germline gain-of-function variants dysregulate RAS-MAPK signaling and cause Noonan syndrome and hereditary gingival fibromatosis.

Disorders

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