RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

Thillaivillalan Dhanaraman, Swati Singh, Ryan C. Killoran, Anamika Singh, Xingjian Xu, Julia M. Shifman, Matthew J. Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Small guanosine triphosphatases (GTPases) of the RAS superfamily signal by directly binding to multiple downstream effector proteins. Effectors are defined by a folded RAS-association (RA) domain that binds exclusively to GTP-loaded (activated) RAS, but the binding specificities of most RA domains toward more than 160 RAS superfamily GTPases have not been characterized. Ten RA domain family (RASSF) proteins comprise the largest group of related effectors and are proposed to couple RAS to the proapoptotic Hippo pathway. Here, we showed that RASSF1-6 formed complexes with the Hippo kinase ortholog MST1, whereas RASSF7-10 formed oligomers with the p53-regulating effectors ASPP1 and ASPP2. Moreover, only RASSF5 bound directly to activated HRAS and KRAS, and RASSFs did not augment apoptotic induction downstream of RAS oncoproteins. Structural modeling revealed that expansion of the RASSF effector family in vertebrates included amino acid substitutions to key residues that direct GTPase-binding specificity. We demonstrated that the tumor suppressor RASSF1A formed complexes with the RAS-related GTPases GEM, REM1, REM2, and the enigmatic RASL12. Furthermore, interactions between RASSFs and RAS GTPases blocked YAP1 nuclear localization. Thus, these simple scaffolds link the activation of diverse RAS family small G proteins to Hippo or p53 regulation.

Original languageAmerican English
Article numbereabb4778
JournalScience Signaling
Volume13
Issue number653
DOIs
StatePublished - 13 Oct 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

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