Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins.
Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), accelerate the growth of gastrointestinal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide and Ggly activate different G proteins of the Rho family of small GTPases. For example, Gamide signals Rac/Cdc42 to activate p21-activated kinase 1 while Ggly signals Rho to activate Rho-activated kinase. p21-activated kinase 1 and Rho-activated kinase induce changes in phosphorylation or expression, respectively, of proteins of the Bcl-2 family, which then affect the caspase cascade with consequent inhibition of apoptosis. In addition, interaction of p21-activated kinase 1 with beta-catenin results in phosphorylation of beta-catenin, which enhances its translocation in to the nucleus, activation of TCF4-dependent transcription, and proliferation and migration. The central role of the beta-catenin pathway in carcinogenesis suggests that specific inhibitors of p21-activated kinase 1 may in the future provide novel therapies for gastrointestinal malignancies.
Department of Surgery, University of Melbourne, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia.
Hong
H
He
Graham S
GS
Baldwin
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005755:Gastrins / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000628:therapy; D054462:p21-Activated Kinases / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D005755:Gastrins; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins