DOI: 10.1126/scisignal.adg5289 ISSN: 1945-0877

RHOA L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling

Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der
  • Cell Biology
  • Molecular Biology
  • Biochemistry

Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr 42 -to-Cys (Y42C) and Leu 57 -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA L57V promotes DGC growth. In mouse gastric organoids with deletion of Cdh1 , which encodes the cell adhesion protein E-cadherin, the expression of RHOA L57V , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr 42 and Leu 57 in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA Y42C . Our results reveal that RHOA L57V and RHOA Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.

More from our Archive