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RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

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Science Signaling  13 Oct 2020:
Vol. 13, Issue 653, eabb4778
DOI: 10.1126/scisignal.abb4778

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Diversity among RASSFs

GTPases of the RAS superfamily couple diverse stimuli to specific downstream pathways by interacting with various effectors that contain RAS-association (RA) domains, such as RA domain family (RASSF) proteins. Although RAS signaling is often associated with cellular proliferation, coupling to the RASSFs has been reported to promote apoptosis. Through binding studies in vitro and in cells, Dhanaraman et al. found that RASSFs 1 to 6 interacted with the Hippo ortholog MST1, and RASSFs 8 to 10 interacted with the p53 regulators ASPP1 and ASPP2. Only RASSF5 interacted with HRAS and KRAS, and RASSF1 interacted with members of the RGK subfamily of RAS GTPases and inhibited nuclear localization of the Hippo-responsive transcription factor YAP. This systematic analysis of RASSF binding partners is a valuable first step in defining the molecular mechanisms through which these RAS effectors couple different RAS family members to proapoptotic pathways.

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.

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