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Submitted on May 11, 2004
Accepted on September 27, 2004
Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4
* To whom correspondence should be addressed. E-mail: d.drucker{at}utoronto.ca.
Glucagon-like peptide-2 regulates proliferative and cytoprotective pathways in the intestine, however GLP-2 receptor (GLP-2R) signal transduction remains poorly understood and cell lines which express the endogenous GLP-2R have not yet been isolated. We have now identified several Expressed Sequence Tags (ESTs) from human cervical carcinoma cDNA libraries which 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 G
s, adenylyl cyclase or transactivation of the EGFR, but was pertussis toxin-sensitive, inhibited by dominant negative Ras, and dependent on 
subunits. GLP-2 also induced a significant increase in BrdU incorporation that was blocked by dominant negative Ras. Furthermore, GLP-2 inhibited HeLa cell apoptosis induced by LY294002 in a PKA-dependent, but ERK-independent manner. These findings demonstrate that the HeLa cell GLP-2R differentially signals through both Gs/cAMP- and Gi/Go-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.
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