Identification of p190RhoGEF in the Gα13 signaling pathway

Abstract

Signaling via GPCRs has been implicated in a myriad of physiological and pathological processes. The G¿12 and G¿13 proteins comprise one of the families of the heterotrimeric G proteins and are known for their regulation of actin cytoskeleton and epithelial cell junctions, as well as in the progression of tumor cells and cancer metastasis. The most extensively characterized downstream mediators of signaling through the G12 subfamily are the members of the Rho family GTPases. G¿12 and G¿13 interact and stimulate the activity of RGS-RhoGEFs sub-family, characterized by their binding to G proteins through their RGS domain. We identified G¿13 as a novel regulatory protein interacting with the non-RGS-RhoGEF p190RhoGEF, known to regulate FAK signaling downstream of GPCRs and involved in promoting tumor progression. We elucidated the involvement of p190RhoGEF in the G¿13 signaling pathway promoting Rho GTPase activation. Moreover, knock-down of G¿13 protein prevents both RhoA activation and paxillin tyrosine phosphorylation upon gastrin stimulation in colon cancer cells. Together, our findings dissect and suggest the existence of a new molecular mechanism of signal transduction through the gastrin-CCK2R and suggest a crucial role of G¿13 in the activation of p190RhoGEF and, probably, in the regulation of neuroendocrine and colon cancer motility and invasion. According to the obtained results, the possible benefit of targeting G¿13 to inhibit gastrin action as a therapy in several gastro-intestinal diseases to treat cancers expressing the CCK2R should be considered.