GLUCOSE, OTHER SECRETAGOGUES, AND NERVE GROWTH-FACTOR STIMULATE MITOGEN-ACTIVATED PROTEIN-KINASE IN THE INSULIN-SECRETING BETA-CELL LINE, INS-1

The signaling pathways whereby glucose and hormonal secretagogues regu late insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the gl ucose-responsive beta-cell line INS-1, major secretagogue-stimulated s ignaling pathways converge to activate 44-kDa mitogen-activated protei n (MAP) kinase. Thus, glucose-induced insulin secretion was found to b e associated with a small stimulatory effect on 44-kDa MAP kinase, whi ch was synergistically enhanced by increased levels of intracellular c AMP and by the hormonal secretagogues glucagon-like peptide-1 and pitu itary adenylate cyclase-activating polypeptide. Activation of 44-kDa M AP kinase by glucose was dependent on Ca2+ influx and may in part be m ediated by MEK-1, a MAP kinase kinase. Stimulation of Ca2+ influx by K Cl was in itself sufficient to activate 44-kDa MAP kinase and MEK-1. P horbol ester, an activator of protein kinase C, stimulated 44-kDa MAP kinase by both Ca2+-dependent and -independent pathways. Nerve growth factor, independently of changes in cytosolic Ca2+, efficiently stimul ated 44-kDa MAP kinase without-causing insulin release, indicating tha t activation of this kinase is not sufficient for secretion. In the pr esence of glucose, however, nerve growth factor potentiated insulin se cretion. In INS-1 cells, activation of 44-kDa MAP kinase was partially correlated with the induction of early response genes junB, nur77, an d zif268 but not with stimulation of DNA synthesis, Our findings sugge st a role of 44-kDa MAP kinase in mediating some of the pleiotropic ac tions of secretagogues on the pancreatic beta-cell.