PDZ-RhoGEF Drives Gastrin Releasing Peptide Stimulated Colon Cancer Cell Migration

Gastrin releasing peptide-receptor (GRPR) is ectopically expressed in over 60% of colon cancers. GRPR expression has been correlated with increased colon cancer cell migration. However, the signaling pathway by which GRPR activation leads to increased cancer cell migration is not well understood. We set out to molecularly dissect the GRPR signaling pathways that control colon cancer cell migration through regulation of small GTPase RhoA. Our results show that GRP stimulation activates RhoA predominantly through G13 heterotrimeric G-protein signaling. We also demonstrate that PDZ-RhoGEF (PRG), a member of RGS-homology domain containing guanine nucleotide exchange factors (RH-RhoGEFs), is the predominant activator of RhoA downstream of GRPR. We found that PRG is required for GRP stimulated colon cancer cell migration, through activation of RhoA-ROCK signaling axis. In addition, PRG-RhoA-ROCK pathway also contributes to Cox-2 expression. Increased Cox-2 expression is correlated with increased production of prostaglandin-E2 (PGE2), and Cox-2-PGE2 signaling contributes to total GRPR mediated cancer cell migration. Our analysis reveals that PRG is over-expressed in colon cancer cell lines. Overall, our results have uncovered a key mechanism for GRPR regulated colon cancer cell migration through Gα13-PRG-RhoA-ROCK pathway.