Faculty Collaboration Database

RHOA^L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling. Sci Signal 2023 Dec 19;16(816):eadg5289

Date

12/19/2023

Pubmed ID

38113333

Pubmed Central ID

PMC10791543

DOI

10.1126/scisignal.adg5289

Scopus ID

2-s2.0-85180383446 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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. Tyr⁴²-to-Cys (Y42C) and Leu⁵⁷-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 Tyr⁴² and Leu⁵⁷ 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.

Author List

Schaefer A, Hodge RG, Zhang H, Hobbs GA, Dilly J, Huynh MV, Goodwin CM, Zhang F, Diehl JN, Pierobon M, Baldelli E, Javaid S, Guthrie K, Rashid NU, Petricoin EF, Cox AD, Hahn WC, Aguirre AJ, Bass AJ, Der CJ

Author

Antje Schaefer PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actins
Animals
Guanosine Triphosphate
Humans
Mice
Proto-Oncogene Proteins p21(ras)
Receptor, IGF Type 1
Signal Transduction
Stomach Neoplasms
p21-Activated Kinases
rhoA GTP-Binding Protein