RASA4B

RAS p21 protein activator 4B (RASA4B, ~803 amino acids, ~90 kDa), member of GAP1 family of RasGAPs. Contains modular architecture: two N-terminal C2 domains (Ca2+-dependent phospholipid binding), pleckstrin homology (PH) domain, and C-terminal RasGAP catalytic domain with arginine finger motif. Paralog of RASA4/CAPRI arising from ancient gene duplication. Functions as calcium-regulated GTPase-activating protein that inactivates RAS proteins by accelerating GTP hydrolysis, converting active RAS-GTP to inactive RAS-GDP. Dual substrate specificity for RAS proteins (H-Ras, K-Ras, N-Ras, R-Ras) and potentially RAP1 GTPase. Under basal conditions, predominantly cytosolic. Upon intracellular Ca2+ elevation, C2 domains bind calcium and acidic phospholipids, triggering translocation to plasma membrane where RAS is located. Membrane association activates GAP activity - acts as calcium decoder linking Ca2+ signals to RAS pathway attenuation. Negatively regulates RAS-MAPK and RAS-PI3K signaling cascades. May serve as molecular adaptor linking calcium signaling, RAS/RAP GTPase regulation, and possibly actin-regulating pathways. Expression ubiquitous but tissue-enriched in skeletal muscle, with significant expression in brain, endometrium, and other tissues. By shutting off RAS in response to calcium, integrates growth factor receptor signaling with calcium oscillations. Potential roles in muscle excitation, neuronal activity, immune cell activation, and growth factor/hormone responses where calcium and RAS pathways intersect. May contribute to tumor suppression by restraining oncogenic RAS signaling. Association with pancreatic cancer (favorable prognosis with high expression) and gastric cancer (unfavorable with high expression) suggests context-dependent roles in tumorigenesis.