GLUCOSE, OTHER SECRETAGOGUES, AND NERVE GROWTH-FACTOR STIMULATE MITOGEN-ACTIVATED PROTEIN-KINASE IN THE INSULIN-SECRETING BETA-CELL LINE, INS-1
GLUCOSE, OTHER SECRETAGOGUES, AND NERVE GROWTH-FACTOR STIMULATE MITOGEN-ACTIVATED PROTEIN-KINASE IN THE INSULIN-SECRETING BETA-CELL LINE, INS-1
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DOI：
10.1074/jbc.270.14.7882
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发表时间：
1995-04-07
影响因子：
4.8
通讯作者：
VANOBBERGHEN, E
中科院分区：
文献类型：
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作者：
FRODIN, M;SEKINE, N;VANOBBERGHEN, E
葡萄糖和激素促分泌剂调节胰岛素分泌功能、基因转录和胰腺β细胞增殖的信号通路尚不明确。我们发现，在葡萄糖反应性 β 细胞系 INS-1 中，主要的促分泌素刺激信号通路汇聚以激活 44-kDa 丝裂原激活蛋白 (MAP) 激酶。因此，发现葡萄糖诱导的胰岛素分泌与对 44-kDa MAP 激酶的小刺激作用有关，细胞内 cAMP 水平增加以及激素促分泌剂胰高血糖素样肽-1 和垂体腺苷酸环化酶激活多肽可协同增强这种作用。葡萄糖对 44-kDa MAP 激酶的激活依赖于 Ca2+ 流入，并且可能部分由 MAP 激酶激酶 MEK-1 介导。 KCl 对 Ca2+ 流入的刺激本身足以激活 44-kDa MAP 激酶和 MEK-1。佛波酯是蛋白激酶 C 的激活剂，通过 Ca2+ 依赖性和非依赖性途径刺激 44-kDa MAP 激酶。神经生长因子，独立于胞质 Ca2+ 的变化，有效地刺激 44-kDa MAP 激酶，而不引起胰岛素释放，表明该激酶的激活不足以分泌。然而，在葡萄糖存在的情况下，神经生长因子会增强胰岛素的分泌。在 INS-1 细胞中，44-kDa MAP 激酶的激活与早期反应基因 junB、nur77 和 zif268 的诱导部分相关，但与 DNA 合成的刺激无关。我们的研究结果表明 44-kDa MAP 激酶在介导促分泌剂对胰腺 β 细胞的一些多效性作用中发挥作用。
The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways converge to activate 44-kDa mitogen-activated protein (MAP) kinase. Thus, glucose-induced insulin secretion was found to be associated with a small stimulatory effect on 44-kDa MAP kinase, which was synergistically enhanced by increased levels of intracellular cAMP and by the hormonal secretagogues glucagon-like peptide-1 and pituitary adenylate cyclase-activating polypeptide. Activation of 44-kDa MAP kinase by glucose was dependent on Ca2+ influx and may in part be mediated by MEK-1, a MAP kinase kinase. Stimulation of Ca2+ influx by KCl was in itself sufficient to activate 44-kDa MAP kinase and MEK-1. Phorbol 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 stimulated 44-kDa MAP kinase without-causing insulin release, indicating that activation of this kinase is not sufficient for secretion. In the presence of glucose, however, nerve growth factor potentiated insulin secretion. In INS-1 cells, activation of 44-kDa MAP kinase was partially correlated with the induction of early response genes junB, nur77, and zif268 but not with stimulation of DNA synthesis, Our findings suggest a role of 44-kDa MAP kinase in mediating some of the pleiotropic actions of secretagogues on the pancreatic beta-cell.