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

Abstract

Activation of glucagon-like peptide-2 receptor (GLP-2R

Herpes simplex virus protein kinase U S 3 activates and functionally overlaps protein kinase A to block apoptosis

“…(i) Extensive literature indicates that PKA plays an important role in regulating apoptosis in eukaryotic cells (21)(22)(23)(24). The data presented in this report indicates that in the experimental context used in these studies, activated PKA performed the same functions as the U S 3 protein kinase in blocking apoptosis induced by either a replication deficient virus or a proapoptotic cellular protein.…”

“…This sequence closely resembles the target sequence of the cellular cAMP-dependent protein kinase PKA (20). Interestingly, extensive literature indicates that PKA is a key enzyme important in the regulation of metabolism, survival, and proliferation of eukaryotic cells, and it mediates most of the biological effects of the second messenger cAMP (20)(21)(22)(23)(24)(25). Structurally, the enzyme is an inactive tetramer composed of two regulatory (R) and two catalytic subunits.…”

Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells

“…Similarly, GLP-1 treatment prevents chemically-induced apoptosis in association with enhanced total PKB levels in baby hamster kidney fibroblasts transfected with the GLP-1 receptor [19]. However, in the same cells transfected with the GLP-2 receptor, inhibition of apoptosis by GLP-2 appears to be PKB-independent [44]. Finally, PTHrP exerts both pro-and anti-apoptotic effects on osteoblasts, with the direction of the effect dependent on cell number [45].…”

Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21CIP1/WAF1 induction rather than AKT inhibition

“…In the case of LY/HDI-mediated apoptois, an alternative possibility is that LY may disrupt one or more PI-3 kinase-dependent, Aktindependent pathways, that is, CDC42, RAC1, or the serum and glucocorticoid-inducible kinase (SGK), among others (Park et al, 1999;Murga et al, 2002). For example, the prosurvival effects of glugagon-like peptide-2 (GLP-2) on LY294002-induced cell death in hamster kidney cells has recently been shown to involve PKA-dependent but Akt-independent events (Yusta et al, 2002). Whether interference with any of these PI-3 kinase-dependent, Akt-independent pathways is responsible for potentiation of HDI-mediated lethality by LY remains to be determined.…”