Alterations in Receptor Expression or Agonist Concentration Change the Pathways Gastrin-Releasing Peptide Receptor Uses to Regulate Extracellular Signal-Regulated Kinase
- 10 September 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 66 (6), 1625-1634
- https://doi.org/10.1124/mol.104.001206
Abstract
G protein-coupled receptors activate extracellular signal-regulated kinases (ERKs) via different pathways in different cell types. In this study, we demonstrate that gastrin-releasing peptide receptor (GRPr) regulates ERK through multiple pathways in a single cell type depending upon receptor expression and agonist concentration. We examined stably transfected BALB/c 3T3 fibroblasts expressing GRPr constructs at different levels and treated the cells with several concentrations of bombesin (BN, a GRPr agonist) to activate a variable number of GRPr per cell. GRPr induced two waves of ERK activation and one wave of ERK inhibition. One wave of activation required an intact GRPr carboxyl-terminal domain (CTD). It peaked 6 min after addition of high BN concentration ([BN]) in cells with high GRPr expression. Another wave of activation was CTD-independent. It peaked 2 to 4 min after BN addition in cells when [BN] and/or GRPr expression were lower. The early wave of ERK activation was more sensitive than the later one to pretreatment with Bisindolylmaleimide I (GF 109203X) (a protein kinase C inhibitor) or hypertonic sucrose. Because these two waves of activation differ in time course, dose-response curve, requirement for GRPr CTD, and sensitivity to inhibitors, they result from different signaling pathways. A third pathway in these cells inhibited ERK phosphorylation 2 min after addition of high [BN] in cells with high GRPr expression. Furthermore, a GRPr-expressing human duodenal cancer cell line showed differential sensitivity to GF 109203X throughout BN-induced ERK activation, indicating that GRPr may activate ERK via multiple pathways in cells expressing endogenous GRPr.Keywords
This publication has 32 references indexed in Scilit:
- Agonist- and Protein Kinase C-Induced Phosphorylation Have Similar Functional Consequences for Gastrin-Releasing Peptide Receptor Signaling via GqPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2003
- Endothelial cell response to different mechanical forcesJournal of Vascular Surgery, 2000
- The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complexProceedings of the National Academy of Sciences, 2000
- Src-mediated Tyrosine Phosphorylation of Dynamin Is Required for β2-Adrenergic Receptor Internalization and Mitogen-activated Protein Kinase SignalingPublished by Elsevier ,1999
- Essential Role for G Protein-coupled Receptor Endocytosis in the Activation of Mitogen-activated Protein KinaseJournal of Biological Chemistry, 1998
- A β-Arrestin/Green Fluorescent Protein Biosensor for Detecting G Protein-coupled Receptor ActivationJournal of Biological Chemistry, 1997
- Bombesin and neuromedin B stimulate the activation of p42mapk and p74raf-1 via a protein kinase C-independent pathway in Rat-1 cellsOncogene, 1997
- Activation of Multiple Mitogen-activated Protein Kinase Signal Transduction Pathways by the Endothelin B Receptor Requires the Cytoplasmic TailJournal of Biological Chemistry, 1996
- The Primary Structure of MEK, a Protein Kinase that Phosphorylates the ERK Gene ProductScience, 1992
- Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancerNature, 1985