Sos1

SOS1, short for Son of Sevenless homolog 1, is a guanine nucleotide exchange factor (GEF) that activates the small GTPase Ras in response to receptor tyrosine kinase signaling. In resting cells, Ras is bound to GDP and inactive; SOS1 facilitates GDP release and GTP binding, thereby converting Ras to its active state and promoting downstream signaling through the Raf-MEK-ERK cascade. Activation is typically triggered when growth factor-bound receptors recruit adaptor proteins such as Grb2, which binds to SOS1 via its SH3-binding proline-rich regions, bringing SOS1 to the plasma membrane where Ras is located.

Domain architecture includes the REM (Ras Exchange Motif) and CDC25 homology domain that catalyze nucleotide exchange, along with regions that mediate membrane localization and protein interactions.

Clinical significance: In humans, germline mutations in SOS1 are associated with Noonan syndrome, a RASopathy characterized by facial features, congenital heart defects, short stature, and developmental delay. Most SOS1 mutations are gain-of-function, enhancing Ras–MAPK signaling. Altered SOS1 activity has also been studied in cancer, where it can contribute to hyperactive Ras signaling in tumors with receptor tyrosine kinase upregulation or Ras mutations.

Research and therapeutic interest: Because SOS1 acts upstream of Ras, inhibitors that block SOS1–GRB2 interaction or SOS1’s catalytic activity are under investigation as potential strategies to dampen Ras-driven signaling in cancer, particularly where direct Ras inhibitors are ineffective.

Biological role: SOS1 is widely expressed and functions in various tissues to regulate cell proliferation, differentiation, and survival through the Ras-MAPK pathway.