Gain-of-Function RHOA Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer.

ABSTRACT: Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOA^Y42C, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOA^Y42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOA^Y42C exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. RHOA ^Y42C mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which

SUBMITTER: Zhang H 

PROVIDER: S-EPMC7007383 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature