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J Biol Chem, Vol. 274, Issue 43, 30459-30467, October 22, 1999
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From the Glucagon-like peptide-2 (GLP-2) promotes the
expansion of the intestinal epithelium through stimulation of the GLP-2
receptor, a recently identified member of the glucagon-secretin G
protein-coupled receptor superfamily. Although activation of G
protein-coupled receptors may lead to stimulation of cell growth, the
mechanisms transducing the GLP-2 signal to mitogenic proliferation
remain unknown. We now report studies of GLP-2R signaling in baby
hamster kidney (BHK) cells expressing a transfected rat GLP-2 receptor (BHK-GLP-2R cells). GLP-2, but not glucagon or GLP-1, increased the
levels of cAMP and activated both cAMP-response element- and AP-1-dependent transcriptional activity in a
dose-dependent manner. The activation of AP-1-luciferase
activity was protein kinase A (PKA) -dependent and markedly
diminished in the presence of a dominant negative inhibitor of PKA.
Although GLP-2 stimulated the expression of c-fos,
c-jun, junB, and zif268, and transiently increased p70 S6 kinase in quiescent BHK-GLP-2R cells, GLP-2 also inhibited extracellular signal-regulated kinase 1/2 and reduced serum-stimulated Elk-1 activity. Furthermore, no rise in intracellular calcium was observed following GLP-2 exposure in BHK-GLP-2R cells. Although GLP-2 stimulated both cAMP accumulation and cell
proliferation, 8-bromo-cyclic AMP alone did not promote cell
proliferation. These findings suggest that the GLP-2R may be coupled to
activation of mitogenic signaling in heterologous cell types
independent of PKA via as yet unidentified downstream mediators of
GLP-2 action in vivo.
Department of Medicine, The Toronto General
Hospital, University of Toronto, Toronto, Ontario M5G 2C4, Canada,
the Departments of § Cell Biology and Physiology,
Hospital for Sick Children, University of Toronto,
Toronto, Ontario M5G 2C4, Canada, and ¶ Allelix
Biopharmaceuticals Inc., Mississauga, Ontario L4V 1P1, Canada
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