Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Manner and Prevents Apoptosis following Inhibition of Phosphatidylinositol 3-Kinase
Copyright policy )Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Manner and Prevents Apoptosis following Inhibition of Phosphatidylinositol 3-Kinase
Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling promotes expansion of the mucosal epithelium indirectly via activation of growth and anti-apoptotic pathways; however, the cellular mechanisms coupling direct GLP-2R activation to cell survival remain poorly understood. We now demonstrate that GLP-2, in a cycloheximide-insensitive manner, enhanced survival in baby hamster kidney cells stably transfected with the rat GLP-2R; reduced mitochondrial cytochrome c efflux; and attenuated the caspase-dependent cleavage of Akt, poly(ADP-ribose) polymerase, and beta-catenin following inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002. The prosurvival effects of GLP-2 on LY294002-induced cell death were independent of Akt, p90(Rsk), or p70 S6 kinase activation; were mimicked by forskolin; and were abrogated by inhibition of protein kinase A (PKA) activity. GLP-2 inhibited activation of glycogen synthase kinase-3 (GSK-3) through phosphorylation at Ser(21) in GSK-3alpha and at Ser(9) in GSK-3beta in a PI3K-independent, PKA-dependent manner. GLP-2 reduced LY294002-induced mitochondrial association of endogenous Bad and Bax and stimulated phosphorylation of a transfected Bad fusion protein at Ser(155) in a PI3K-independent, but H89-sensitive manner, a modification known to suppress Bad pro-apoptotic activity. These results suggest that GLP-2R signaling enhances cell survival independently of PI3K/Akt by inhibiting the activity of a subset of pro-apoptotic downstream targets of Akt in a PKA-dependent manner.
- Toronto General Hospital Canada
- University of Toronto Canada
- University Health Network Canada
Morpholines, Glycogen Synthase Kinases, Apoptosis, Cyclic AMP-Dependent Protein Kinases, Glucagon-Like Peptide-1 Receptor, Cell Line, Glycogen Synthase Kinase 3, Chromones, Cricetinae, Calcium-Calmodulin-Dependent Protein Kinases, Receptors, Glucagon, Animals, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors
Morpholines, Glycogen Synthase Kinases, Apoptosis, Cyclic AMP-Dependent Protein Kinases, Glucagon-Like Peptide-1 Receptor, Cell Line, Glycogen Synthase Kinase 3, Chromones, Cricetinae, Calcium-Calmodulin-Dependent Protein Kinases, Receptors, Glucagon, Animals, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors
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