Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1
Laura D’Andrea, Christina M. Lucato, Elsa A. Marquez, Yong‐Gang Chang, Srgjan Civciristov, Chantel Mastos, Christopher J. Lupton, Cheng Huang, Hans Elmlund, Ralf B. Schittenhelm, Christina A. Mitchell, James C. Whisstock, Michelle L. Halls, Andrew M. Ellisdon
Abstract
hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gβγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.