Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells.
Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for beta-cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for beta-cells, using the well-differentiated beta-cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metabolism and calcium influx and were tightly linked by multiple activating and inhibiting cross-talk. These interactions included: (i) a central role of tyrosine phosphorylation for stimulation of PKA/CREB, MAPK and PI3-kinase/PKB, (ii) inhibition of PKA/CREB by the MAPK pathway at the level of MAPK kinase-1 or downstream, (iii) activation of MAPK signaling by PI3-kinase and PKA at the level of extracellular-signal regulated kinase 1/2 or upstream, and (iv) activation of PKB by MAPK and PKA signaling at the level of PKB or upstream. Furthermore, we demonstrated inhibition of CREB signaling by Ca(2+)/calmodulin kinase I/IV. These results indicated that GIP acts as a mitogenic and anti-apoptotic factor for beta-cells by pleiotropic activation of tightly linked signaling pathways in beta-cells.
Trümper
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Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Philipps-University, Baldingerstrasse, D-35033 Marburg, Germany.
Trümper
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Hörsch
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000496:Alloxan / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003847:Deoxyglucose / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D005941:Glucokinase / Q000037:antagonists & inhibitors; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D008938:Mitosis / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D000077191:Wortmannin; D000096926:Benzenesulfonamides
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000496:Alloxan; D000730:Androstadienes; D001119:Arginase; D001596:Benzylamines; D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002614:Chelating Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D003847:Deoxyglucose; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005749:Gastric Inhibitory Polypeptide; D019833:Genistein; D005941:Glucokinase; D005947:Glucose; D007211:Indoles; D007546:Isoquinolines; D048369:MAP Kinase Kinase 1; D008301:Maleimides; D020929:Mitogen-Activated Protein Kinase Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D013449:Sulfonamides; D000077191:Wortmannin; C072105:KN 93; D000096926:Benzenesulfonamides; C063302:KN 62; C482125:MAP2K1 protein, human; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one