The Rho Guanosine 5′-Triphosphatase, Cell Division Cycle 42, Is Required for Insulin-Induced Actin Remodeling and Glucagon-Like Peptide-1 Secretion in the Intestinal Endocrine L Cell
The Rho Guanosine 5′-Triphosphatase, Cell Division Cycle 42, Is Required for Insulin-Induced Actin Remodeling and Glucagon-Like Peptide-1 Secretion in the Intestinal Endocrine L Cell
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DOI：
10.1210/en.2009-0508
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Brubaker, Patricia L.
中科院分区：
文献类型：
--
作者：
Lim, Gareth E.;Xu, Molie;Brubaker, Patricia L.
Rho gtpase，如细胞分裂周期42 （Cdc42）和ras相关的C3肉毒毒素底物1 (Rac1)，已被确定为f -肌动蛋白动力学和内分泌细胞激素释放的调节因子；然而，它们在肠内分泌L细胞分泌胰高血糖素样肽-1 （GLP-1）中的作用尚不清楚。胰岛素诱导L细胞GLP-1释放增加1.4倍；然而，在f -肌动蛋白解聚剂latrunculin B的存在下，其分泌量增加了2.1倍，这表明f -肌动蛋白起着允许屏障的作用。在小鼠GLUTag L细胞中，胰岛素同时刺激f -肌动蛋白解聚和Cdc42激活，这些事件发生在胰岛素诱导的GLP-1释放增加之前。胰岛素治疗后，也检测到Cdc42依赖性p21活化激酶-1 （PAK1）的活化，转染Cdc42或显性阴性Cdc42（T17N）的小干扰RNA会损害胰岛素刺激的PAK1活化、肌动蛋白重塑和GLP-1分泌。激酶死亡的PAK1（K299R）或PAK1小干扰RNA的过度表达同样会减弱胰岛素诱导的GLP-1分泌。敲低或抑制Cdc42和PAK1活性也可以阻止胰岛素激活MAPK/ERK (MEK)-1/2-ERK1/2，这是胰岛素调节GLP-1释放的关键途径。综上所述，这些数据在内分泌L细胞中发现了一个新的信号通路，Cdc42调节肌动蛋白重塑，激活典型的1/2-ERK1/2通路和PAK1，以及GLP-1分泌以响应胰岛素。（内分泌学150:5249-5261,2009）
Rho GTPases, such as cell division cycle 42 (Cdc42) and ras-related C3 botulinum toxin substrate 1 (Rac1), have been identified as regulators of F-actin dynamics and hormone release from endocrine cells; however, their role in secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), from the enteroendocrine L cell is unknown. Insulin induced a 1.4-fold increase in L cell GLP-1 release; however, secretion was potentiated to 2.1-fold in the presence of the F-actin depolymerizing agent, latrunculin B, suggesting that F-actin functions as a permissive barrier. In murine GLUTag L cells, insulin stimulated F-actin depolymerization and Cdc42 activation simultaneously, and these events occurred prior to detectable increases in insulin-induced GLP-1 release. After insulin treatment, Cdc42-dependent p21-activated kinase-1 (PAK1) activation was also detected, and transfection of small-interfering RNA against Cdc42 or of dominant-negative Cdc42(T17N) impaired insulin-stimulated PAK1 activation, actin remodeling, and GLP-1 secretion. Overexpression of kinase-dead PAK1(K299R) or PAK1 small interfering RNA similarly attenuated insulin-induced GLP-1 secretion. Knockdown or inhibition of Cdc42 and PAK1 activities also prevented activation of MAPK/ERK (MEK)-1/2-ERK1/2 by insulin, which was previously identified as a critical pathway for insulin-regulated GLP-1 release. Taken together, these data identify a novel signaling pathway in the endocrine L cell, whereby Cdc42 regulates actin remodeling, activation of the cannonical 1/2-ERK1/2 pathway and PAK1, and GLP-1 secretion in response to insulin. (Endocrinology 150: 5249-5261, 2009)