Article

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

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2002; 277(28):24896-906. DOI: 10.1074/jbc.M201358200
Source: PubMed

ABSTRACT

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.

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Available from: Jennifer L Estall, Jun 11, 2014
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    • "Similarly, GLP-2 increased cell survival following cycloheximide in the presence of the MAP kinase inhibitor PD98054 and the phosphatidylinositol 3-kinase inhibitor LY294002 (Yusta et al., 2000). The anti-apoptotic actions of the rat GLP-2 receptor in transfected cells are not strictly dependent on phosphatidylinositol 3-kinase (PI3-K) or Akt, as GLP-2 directly promotes cell survival, enhances glycogen synthase kinase-3 and BAD phosphorylation, and reduces mitochondrial-associated BAD and Bax following LY294002-induced apoptosis in a PKAdependent manner (Yusta et al., 2002). More importantly, along with its effects upon cell survival it has recently been shown that GLP-2-stimulated PKA activity can significantly reduce glutamate-induced excitotoxic injury in hippocampal cells. "
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    • "The GLP-2R is expressed in human enteroendocrine cells (Yusta et al., 2000b), murine enteric neurons (Bjerknes and Cheng, 2001), and in specific regions of the central nervous system (Tang-Christensen et al., 2000; Lovshin et al., 2001). Agonist-induced activation of the GLP-2R is coupled to generation of cAMP (Yusta et al., 1999) and leads to enhanced cell survival via inhibition of the proapoptotic molecules GSK3 and Bad (Yusta et al., 2002). GPCRs share a common regulatory pathway that governs agonist-induced desensitization and endocytosis. "
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    • "Similarly, GLP-2 increased cell survival following cycloheximide in the presence of the MAP kinase inhibitor PD98054 and phosphatidylinositol 3-kinase inhibitor LY294002 (Yusta et al., 2000a). The anti-apoptotic actions of the rat GLP-2 receptor in transfected BHK fibroblasts are not strictly dependent on phosphatidylinositol 3-kinase or Akt, as GLP-2 directly promotes cell survival, enhances glycogen synthase kinase-3 and BAD phosphorylation, and reduces mitochondrial-associated BAD and Bax following LY294002-induced apoptosis in a PKA-dependent manner (Yusta et al., 2002). "
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