RhoA has been identified as having a gain-of-function mutation in approximately 20% of diffuse gastric cancer patients. However， the carcinogenic role of RhoA mutations in gastric cancer (GC) is unclear. In the present study， we report that RhoA directly interacts with c-Met and can be phosphorylated by c-Met at Y42 before subsequent K48-linked polyubiquitination and proteasome-mediated protein degradation. Y42C-mutated RhoA exhibits higher protein levels and promotes the proliferation and motility of GC cells. Interestingly， a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT RhoA but not RhoA mutated at Y42 in vivo and in vitro. Analyses of human GC tissues showed that t... More
RhoA has been identified as having a gain-of-function mutation in approximately 20% of diffuse gastric cancer patients. However， the carcinogenic role of RhoA mutations in gastric cancer (GC) is unclear. In the present study， we report that RhoA directly interacts with c-Met and can be phosphorylated by c-Met at Y42 before subsequent K48-linked polyubiquitination and proteasome-mediated protein degradation. Y42C-mutated RhoA exhibits higher protein levels and promotes the proliferation and motility of GC cells. Interestingly， a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT RhoA but not RhoA mutated at Y42 in vivo and in vitro. Analyses of human GC tissues showed that the combined levels of p-c-Met and p-RhoA are a better predictor for prognosis than either factor alone. Taken together， our findings unravel the mechanism by which the RhoA Y42 mutant is linked to poor prognosis in GC. Moreover， this study helps to identify a strategy for patient stratification and optimization of targeted c-Met therapy. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons， Ltd.
