RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

Abstract

Activated RAS GTPases signal by directly binding effector proteins. Effectors have a folded RAS association (RA) domain that binds exclusively to GTP-loaded RAS, but the specificity of most RA domains for >150 RAS superfamily GTPases is unknown. Ten RAS-association domain family (RASSF) proteins comprise the largest group of effectors, proposed to couple RAS to the pro-apoptotic Hippo pathway. We show that RASSF1-6 complex with Hippo kinase, while RASSF7-10 are a separate family related to p53-regulatory ASPP effectors. Only RASSF5 directly binds activated HRAS and KRAS. Structural modelling reveals that expansion of RASSFs in vertebrates included amino acid substitutions that alter their GTPase binding specificity. We demonstrate that the tumour suppressor RASSF1A complexes with the GTPases GEM, REM1, REM2 and the enigmatic RASL12. Interplay between RASSFs and RAS GTPases can drastically restrict YAP1 nuclear localization. Thus, these simple scaffolds can link activation of diverse RAS proteins to Hippo or p53 regulation.