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Mitogenic Signaling via G Protein-Coupled Receptors

TIM van BIESEN^*, LOUIS M. LUTTRELL, BRIAN E. HAWES and ROBERT J. LEFKOWITZ

Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center Durham, North Carolina 27710

Correspondence: Address reprint requests to: Robert J. Lefkowitz, M.D., Howard Hughes Medical Institute, Department of Medicine, Box 3821, Duke University Medical Center, Durham, North Carolina 27710.

Abstract

I. Introduction: RECEPTORS coupled to heterotrimeric GTP-binding proteins (G proteins) comprise the largest known family of cell surface receptors and mediate cellular responses to a diverse array of signaling molecules, including peptide and glycopeptide hormones, neurotransmitters, phospholipids, odorants, and photons. The basic unit of G protein-coupled receptor (GPCR) signaling is comprised of three parts; receptor, which detects ligand in the extracellular milieu; heterotrimeric G protein, which is dissociated into active G-GTP and Gβ-subunits after interaction with the liganded receptor; and effector, which interacts with dissociated G-GTP and Gβ-subunits to mediate the intracellular effects of ligand binding. In a given cell type, the responsiveness to stimulus, as well as the nature of the response, is dictated by the available complement of receptor, G protein, and effector.

Despite the diverse array of ligands with which they interact, GPCRs share a conserved predicted tertiary structure characterized by seven transmembrane domains joined by intracellular and extracellular loops. G protein coupling specificity is dictated by the intracellular domains, particularly the second and third intracellular loops and the Cterminal tail. Indeed, it is possible to alter the G proteincoupling specificity of GPCRs by exchanging relatively small regions within the third intracellular loop (1).

Footnotes

^* Recipient of a Postdoctoral Fellowship from the Alberta Heritage Foundation for Medical Research. Present address: Neuroscience Research, Abbott Laboratories, D-4PM, AP10,100 Abbott Park Road, Abbott Park, Illinois 60064-3500

Recipient of a NIH Clinical Investigator Development Award.

Present address: Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey, 07033.

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				S. M. Short, J. L. Boyer, and R. L. Juliano Integrins Regulate the Linkage between Upstream and Downstream Events in G Protein-coupled Receptor Signaling to Mitogen-activated Protein Kinase J. Biol. Chem., April 21, 2000; 275(17): 12970 - 12977. [Abstract] [Full Text] [PDF]

				R. Grosse, S. Roelle, A. Herrlich, J. Hohn, and T. Gudermann Epidermal Growth Factor Receptor Tyrosine Kinase Mediates Ras Activation by Gonadotropin-releasing Hormone J. Biol. Chem., April 14, 2000; 275(16): 12251 - 12260. [Abstract] [Full Text] [PDF]

				W. E. Miller, S. Maudsley, S. Ahn, K. D. Khan, L. M. Luttrell, and R. J. Lefkowitz beta -Arrestin1 Interacts with the Catalytic Domain of the Tyrosine Kinase c-SRC. ROLE OF beta -ARRESTIN1-DEPENDENT TARGETING OF c-SRC IN RECEPTOR ENDOCYTOSIS J. Biol. Chem., April 6, 2000; 275(15): 11312 - 11319. [Abstract] [Full Text] [PDF]

				E. L. Greene, O. Houghton, G. Collinsworth, M. N. Garnovskaya, T. Nagai, T. Sajjad, V. Bheemanathini, J. S. Grewal, R. V. Paul, and J. R. Raymond 5-HT2A receptors stimulate mitogen-activated protein kinase via H2O2 generation in rat renal mesangial cells Am J Physiol Renal Physiol, April 1, 2000; 278(4): F650 - F658. [Abstract] [Full Text] [PDF]

				V. Antonelli, F. Bernasconi, Y. H. Wong, and L. Vallar Activation of B-Raf and Regulation of the Mitogen-activated Protein Kinase Pathway by the Go alpha chain Mol. Biol. Cell, April 1, 2000; 11(4): 1129 - 1142. [Abstract] [Full Text]

				S. Maudsley, K. L. Pierce, A. M. Zamah, W. E. Miller, S. Ahn, Y. Daaka, R. J. Lefkowitz, and L. M. Luttrell The beta 2-Adrenergic Receptor Mediates Extracellular Signal-regulated Kinase Activation via Assembly of a Multi-receptor Complex with the Epidermal Growth Factor Receptor J. Biol. Chem., March 24, 2000; 275(13): 9572 - 9580. [Abstract] [Full Text] [PDF]

				M. H. Ghahremani, C. Forget, and P. R. Albert Distinct Roles for Galpha i2 and Gbeta gamma in Signaling to DNA Synthesis and Galpha i3 in Cellular Transformation by Dopamine D2S Receptor Activation in BALB/c 3T3 Cells Mol. Cell. Biol., March 1, 2000; 20(5): 1497 - 1506. [Abstract] [Full Text]

				A. Chorvatova, L. Gendron, L. Bilodeau, N. Gallo-Payet, and M. D. Payet A Ras-Dependent Chloride Current Activated by Adrenocorticotropin in Rat Adrenal Zona Glomerulosa Cells Endocrinology, February 1, 2000; 141(2): 684 - 692. [Abstract] [Full Text] [PDF]

				H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H521 - H529. [Abstract] [Full Text] [PDF]

				H. Hallak, A. E. M. Seiler, J. S. Green, B. N. Ross, and R. Rubin Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor. RELEASE OF Gbeta gamma SUBUNITS UPON RECEPTOR ACTIVATION J. Biol. Chem., January 28, 2000; 275(4): 2255 - 2258. [Abstract] [Full Text] [PDF]

				B. Seo, E. W. Choy, S. Maudsley, W. E. Miller, B. A. Wilson, and L. M. Luttrell Pasteurella multocida Toxin Stimulates Mitogen-activated Protein Kinase via Gq/11-dependent Transactivation of the Epidermal Growth Factor Receptor J. Biol. Chem., January 21, 2000; 275(3): 2239 - 2245. [Abstract] [Full Text] [PDF]

				G. Liu, L. Duranteau, J.-C. Carel, J. Monroe, D. A. Doyle, and A. Shenker Leydig-Cell Tumors Caused by an Activating Mutation of the Gene Encoding the Luteinizing Hormone Receptor N. Engl. J. Med., December 2, 1999; 341(23): 1731 - 1736. [Full Text] [PDF]

				S. Keffel, M. Schmidt, A. Bischoff, and M. C. Michel Neuropeptide-Y Stimulation of Extracellular Signal-Regulated Kinases in Human Erythroleukemia Cells J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1172 - 1178. [Abstract] [Full Text]

				W. A. Ricketts, J. H. Brown, and J. M. Olefsky Pertussis Toxin-Sensitive and -Insensitive Thrombin Stimulation of Shc Phosphorylation and Mitogenesis Are Mediated through Distinct Pathways Mol. Endocrinol., December 1, 1999; 13(12): 1988 - 2001. [Abstract] [Full Text]

				M. G. Frid, A. A. Aldashev, R. A. Nemenoff, R. Higashito, J. Y. Westcott, and K. R. Stenmark Subendothelial Cells From Normal Bovine Arteries Exhibit Autonomous Growth and Constitutively Activated Intracellular Signaling Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2884 - 2893. [Abstract] [Full Text] [PDF]

				S. F. Steinberg The Molecular Basis for Distinct {beta}-Adrenergic Receptor Subtype Actions in Cardiomyocytes Circ. Res., November 26, 1999; 85(11): 1101 - 1111. [Full Text] [PDF]

				S. J. Keely and K. E. Barrett ErbB2 and ErbB3 Receptors Mediate Inhibition of Calcium-dependent Chloride Secretion in Colonic Epithelial Cells J. Biol. Chem., November 19, 1999; 274(47): 33449 - 33454. [Abstract] [Full Text] [PDF]

				A. Evdokiou, L.-J. Raggatt, G. J. Atkins, and D. M. Findlay Calcitonin Receptor-Mediated Growth Suppression of HEK-293 Cells Is Accompanied by Induction of p21WAF1/CIP1 and G2/M Arrest Mol. Endocrinol., October 1, 1999; 13(10): 1738 - 1750. [Abstract] [Full Text]

				H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata Endothelin-Mediated Vascular Growth Requires p42/p44 Mitogen-Activated Protein Kinase and p70 S6 Kinase Cascades via Transactivation of Epidermal Growth Factor Receptor Endocrinology, October 1, 1999; 140(10): 4659 - 4668. [Abstract] [Full Text]

				A. J. Morris and C. C. Malbon Physiological Regulation of G Protein-Linked Signaling Physiol Rev, October 1, 1999; 79(4): 1373 - 1430. [Abstract] [Full Text] [PDF]

				N. Dzimiri Regulation of beta -Adrenoceptor Signaling in Cardiac Function and Disease Pharmacol. Rev., September 1, 1999; 51(3): 465 - 502. [Abstract] [Full Text] [PDF]

				M. J. Orsini, V. P. Krymskaya, A. J. Eszterhas, J. L. Benovic, R. A. Panettieri Jr., and R. B. Penn MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L479 - L488. [Abstract] [Full Text] [PDF]

				N. L. Schramm and L. E. Limbird Stimulation of Mitogen-activated Protein Kinase by G Protein-coupled alpha 2-Adrenergic Receptors Does Not Require Agonist-elicited Endocytosis J. Biol. Chem., August 27, 1999; 274(35): 24935 - 24940. [Abstract] [Full Text] [PDF]