Gα₁₃/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

Abstract

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 postsynaptic density 95/disk-large/ZO-1 (PDZ)-RhoGEF (PRG), a member of regulator of G-protein signaling (RGS)-homology domain (RH) 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-Rhoassociated kinase (ROCK) signaling axis. In addition, PRG-RhoA-ROCK pathway also contributes to cyclo-oxygenase isoform 2 (Cox-2) expression. Increased Cox-2 expression is correlated with increased production of prostaglandin-E 2 (PGE 2 ), and Cox-2-PGE 2 signaling contributes to total GRPR-mediated cancer cell migration. Our analysis reveals that PRG is overexpressed in colon cancer cell lines. Overall, our results have uncovered a key mechanism for GRPR-regulated colon cancer cell migration through the Ga 13 -PRG-RhoA-ROCK pathway.

Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway

“…based on a number of studies, upregulated RhoA is associated with tumor progression in different types of cancer (33)(34)(35) and RhoA activation promotes the migration of cervical, colon and hepatocellular carcinoma (36)(37)(38). However, significantly downregulated expression of RhoA was demonstrated in human conventional RCC compared to that in normal kidney tissues (17) and activated RhoA has specifically been shown to inhibit the migration of breast and prostate cancer (39,40).…”

Insights into bombesin receptors and ligands: Highlighting recent advances

“…This is primarily accomplished through coupling to the Gq/11 and G12/13 families of heterotrimeric G-proteins [129,255,298]. BnR’s activation stimulate a number of other signaling cascades including activation of Phospholipase D and A2, small GTP binding proteins such as Rho, protein kinase D and various ion channels [111,129,326,354,397].…”

Bombesin receptor subtype 3 as a potential target for obesity and diabetes

“…In the case of GRPR and NMBR, PLC activation has been studied in more detail and is primarily accomplished through coupling to the Gq/11 and G12/13 families of heterotrimeric G-proteins[8,9,41]. Activation of GRPR and NMBR, as well as in many cases also BRS-3, have been shown to stimulate a number of other signaling cascades including activation of Phospholipase D and A2, small GTP binding proteins such as Rho, protein kinase D and various ion channels[8,9,28,41–44]. …”