RASA1

RASA1 (RAS p21 protein activator 1, also known as p120RasGAP or p120GAP) is the prototypical Ras GTPase-activating protein that negatively regulates Ras signaling by stimulating the intrinsic GTPase activity of Ras, converting active Ras-GTP to inactive Ras-GDP. The protein contains a modular architecture with N-terminal tandem SH2 domains, an atypical SH3 domain, and central PH and C2 domains that mediate membrane recruitment via phosphotyrosine binding and lipid interactions. The C-terminal catalytic RasGAP domain contains an essential arginine finger (Arg-789) that stabilizes the transition state during GTP hydrolysis. RASA1 is recruited to activated receptor tyrosine kinases (including PDGFR, EGFR, and EphB4) via its SH2 domains, thereby constraining Ras-mediated RAF-MEK-ERK and PI3K-AKT signaling. Beyond its GAP activity, RASA1 serves as a signaling scaffold through interactions with p190RhoGAP (ARHGAP35) and DLC1, linking Ras and Rho pathway crosstalk. Germline loss-of-function mutations cause capillary malformation-arteriovenous malformation syndrome (CM-AVM1), highlighting its essential role in vascular development and endothelial cell function. The protein also has a documented anti-apoptotic function through caspase-mediated cleavage generating fragment N, which activates Akt to promote cell survival under stress conditions.

Disorders

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