| First Author | Song H | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 8 | Pages | 5528-41 |
| PubMed ID | 22194610 | Mgi Jnum | J:182443 |
| Mgi Id | MGI:5315646 | Doi | 10.1074/jbc.M111.285114 |
| Citation | Song H, et al. (2012) Group VIA PLA2 (iPLA2beta) is activated upstream of p38 mitogen-activated protein kinase (MAPK) in pancreatic islet beta-cell signaling. J Biol Chem 287(8):5528-41 |
| abstractText | Group VIA phospholipase A(2) (iPLA(2)beta) in pancreatic islet beta-cells participates in glucose-stimulated insulin secretion and sarco(endo)plasmic reticulum ATPase (SERCA) inhibitor-induced apoptosis, and both are attenuated by pharmacologic or genetic reductions in iPLA(2)beta activity and amplified by iPLA(2)beta overexpression. While exploring signaling events that occur downstream of iPLA(2)beta activation, we found that p38 MAPK is activated by phosphorylation in INS-1 insulinoma cells and mouse pancreatic islets, that this increases with iPLA(2)beta expression level, and that it is stimulated by the iPLA(2)beta reaction product arachidonic acid. The insulin secretagogue D-glucose also stimulates beta-cell p38 MAPK phosphorylation, and this is prevented by the iPLA(2)beta inhibitor bromoenol lactone. Insulin secretion induced by d-glucose and forskolin is amplified by overexpressing iPLA(2)beta in INS-1 cells and in mouse islets, and the p38 MAPK inhibitor PD169316 prevents both responses. The SERCA inhibitor thapsigargin also stimulates phosphorylation of both beta-cell MAPK kinase isoforms and p38 MAPK, and bromoenol lactone prevents both events. Others have reported that iPLA(2)beta products activate Rho family G-proteins that promote MAPK kinase activation via a mechanism inhibited by Clostridium difficile toxin B, which we find to inhibit thapsigargin-induced beta-cell p38 MAPK phosphorylation. Thapsigargin-induced beta-cell apoptosis and ceramide generation are also prevented by the p38 MAPK inhibitor PD169316. These observations indicate that p38 MAPK is activated downstream of iPLA(2)beta in beta-cells incubated with insulin secretagogues or thapsigargin, that this requires prior iPLA(2)beta activation, and that p38 MAPK is involved in the beta-cell functional responses of insulin secretion and apoptosis in which iPLA(2)beta participates. |
