This Article Full Text Full Text (PDF) All Versions of this Article: 19/2/459    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koehler, J. A. Articles by Drucker, D. J. Search for Related Content PubMed PubMed Citation Articles by Koehler, J. A. Articles by Drucker, D. J.

The HeLa Cell Glucagon-Like Peptide-2 Receptor Is Coupled to Regulation of Apoptosis and ERK1/2 Activation through Divergent Signaling Pathways

Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. Daniel J. Drucker, Toronto General Hospital, Banting and Best Diabetes Centre, 200 Elizabeth Street, MBRW4R-402, Toronto, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca.

Glucagon-like peptide-2 (GLP-2) regulates proliferative and cytoprotective pathways in the intestine; however GLP-2 receptor (GLP-2R) signal transduction remains poorly understood, and cell lines that express the endogenous GLP-2R have not yet been isolated. We have now identified several expressed sequence tags from human cervical carcinoma cDNA libraries that correspond to GLP-2R nucleotide sequences. GLP-2R mRNA transcripts were detected by RT-PCR in two human cervical carcinoma cell lines, including HeLa cells. GLP-2 increased cAMP accumulation and activated ERK1/2 in HeLa cells transiently expressing the cloned human HeLa cell GLP-2R cDNA. However, the GLP-2R-induced activation of ERK1/2 was not mediated through Gs, adenylyl cyclase, or transactivation of the epidermal growth factor receptor, but was pertussis toxin sensitive, inhibited by dominant negative Ras, and dependent on ß-subunits. GLP-2 also induced a significant increase in bromodeoxyuridine incorporation that was blocked by dominant negative Ras. Furthermore, GLP-2 inhibited HeLa cell apoptosis induced by LY294002 in a protein kinase A-dependent, but ERK-independent, manner. These findings demonstrate that the HeLa cell GLP-2R differentially signals through both Gs/cAMP- and G_i/G_o-dependent pathways, illustrating for the first time that the GLP-2R is capable of coupling to multiple heterotrimeric G proteins defining distinct GLP-2R-dependent biological actions.

This article has been cited by other articles:

				P. E. Dube and P. L. Brubaker Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E460 - E465. [Abstract] [Full Text] [PDF]

				D. G. Burrin, B. Stoll, X. Guan, L. Cui, X. Chang, and D. Hadsell GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E281 - E291. [Abstract] [Full Text] [PDF]

				E. M Sinclair and D. J. Drucker Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential Physiology, October 1, 2005; 20(5): 357 - 365. [Abstract] [Full Text] [PDF]

				J. L. Estall, J. A. Koehler, B. Yusta, and D. J. Drucker The Glucagon-like Peptide-2 Receptor C Terminus Modulates {beta}-Arrestin-2 Association but Is Dispensable for Ligand-induced Desensitization, Endocytosis, and G-protein-dependent Effector Activation J. Biol. Chem., June 10, 2005; 280(23): 22124 - 22134. [Abstract] [Full Text] [PDF]