The Ras/p120 GTPase-activating protein (GAP) interaction is regulated by the p120 GAP pleckstrin homology domain

Pleckstrin homology domains are structurally conserved functional domains t hat can undergo both protein/protein and protein/lipid interactions. Plecks trin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including man y that interact with Pas superfamily members, such as p120 GAP, The pleckst rin homology domain of p120 GAP is located in the NH2-terminal, noncatalyti c region of p120 GAP. Overexpression of the noncatalytic domains of p120 GA P may modulate Pas signal transduction pathways. Here, we demonstrate that expression of the isolated pleckstrin homology domain of p120 GAP specifica lly inhibits Pas-mediated signaling and transformation but not normal cellu lar growth. Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interactio n. Thus, we suggest that the pleckstrin homology domain of p120 GAP may spe cifically regulate the interaction of Pas with p120 GAP via competitive int ramolecular binding.