Functional Cross-talk between Ras and Rho Pathways: A Ras-SPECIFIC GTPase-ACTIVATING PROTEIN (p120RasGAP) COMPETITIVELY INHIBITS THE RhoGAP ACTIVITY OF DELETED IN LIVER CANCER (DLC) TUMOR SUPPRESSOR BY MASKING THE CATALYTIC ARGININE FINGER

摘要: The three deleted in liver cancer genes (DLC1–3) encode Rho-specific GTPase-activating proteins (RhoGAPs). Their expression is frequently silenced a variety of cancers. RhoGAP activity, which required for full DLC-dependent tumor suppressor can be inhibited by the Src homology 3 (SH3) domain Ras-specific GAP (p120RasGAP). Here, we comprehensively investigated molecular mechanism underlying cross-talk between two distinct regulators small GTP-binding using structural and biochemical methods. We demonstrate that only SH3 p120 selectively inhibits activity all DLC isoforms as compared with large set other representative or proteins. Structural mutational analyses provide new insights into putative interaction mode DLC1 atypical does not follow classical PXXP-directed interaction. Hence, associates targeting catalytic arginine finger thus competitively very potently inhibiting activity. novel findings this study shed light on mechanisms inhibitory effects suggest functional Ras Rho at level regulatory