title: 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-Rho-associated 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-E2 (PGE2), and Cox-2-PGE2 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 Gα13-PRG-RhoA-ROCK pathway.
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
authors: Maulik
authors: M
authors: Patel
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
authors: Takeharu
authors: T
authors: Kawano
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
authors: Nobuchika
authors: N
authors: Suzuki
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
authors: Takao
authors: T
authors: Hamakubo
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.).
authors: Andrei V
authors: AV
authors: Karginov
authors: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, Illinois (M.P., A.V.K., T.Ko.); Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia (T. Ka.); and Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan (N.S., T.H., T.Ko.). karginov@uic.edu kozasa@lsbm.org.
authors: Tohru
authors: T
authors: Kozasa
mesh_terms: D018938:Caco-2 Cells; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D000076122:Disks Large Homolog 4 Protein; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018004:Receptors, Bombesin / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018004:Receptors, Bombesin; D064067:Rho Guanine Nucleotide Exchange Factors; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C066737:RHOA protein, human; D051546:Cyclooxygenase 2; D054460:rho-Associated Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein; D015232:Dinoprostone