GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins
GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins
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DOI：
10.1016/j.cellsig.2014.04.012
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发表时间：
2014-08-01
影响因子：
4.8
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Chen, Qiaoli;Quan, Chao;Chen, Shuai
胰岛素和肌肉收缩均刺激葡萄糖转运蛋白GLUT4向骨骼肌质膜转运，这是调节全身葡萄糖稳态的重要过程。RalA介导胰岛素刺激的GLUT4易位；然而，目前尚不清楚这种小的GTPase是如何在骨骼肌中对胰岛素的反应进行调节的。在这里，我们确定了骨骼肌中Ral-GTPase激活蛋白的一个主要亚基GARNL1/RalGAP α 1，该蛋白的磷酸化和与14-3-3调节蛋白的结合受到胰岛素和肌肉收缩的刺激。胰岛素刺激与14-3-3的相互作用涉及PKB/ akt介导的GARNL1/RalGAP α 1上Thr（735）的磷酸化。GARNL1/RalGAP α 1的敲低增加，而GARNL1/RalGAP α 1 （Thr735Ala）突变蛋白的过表达减少，RalA激活和RalA依赖的GLUT4易位在肌肉细胞中响应胰岛素。这些发现表明，在肌肉细胞中，GARNL1/RalGAP α 1是连接胰岛素- pkb /Akt信号通路与RalA小GTPase激活的缺失环节。GARNL1/RalGAP α 1及其磷酸化和/或与14-3-3的结合对于GLUT4在肌肉细胞中通过RalA运输至关重要。(C) 2014爱思唯尔公司版权所有。
Insulin and muscle contraction each stimulate translocation of the glucose transporter GLUT4 to the plasma membrane in skeletal muscle, an important process regulating whole-body glucose homeostasis. RalA mediates insulin-stimulated GLUT4 translocation; however, it is unclear how this small GTPase is regulated in skeletal muscle in response to insulin. Here, we identified GARNL1/RalGAP alpha 1, a major a subunit of the Ral-GTPase activating protein in skeletal muscle, as a protein whose phosphorylation and binding to the regulatory 14-3-3 proteins is stimulated by insulin and also by muscle contraction. The insulin-stimulated interaction with 14-3-3 involved PKB/Akt-mediated phosphorylation of Thr(735) on GARNL1/RalGAP alpha 1. Knockdown of GARNL1/RalGAP alpha 1 increased, while overexpression of GARNL1/RalGAP alpha 1 (Thr735Ala) mutant protein decreased, the RalA activation and the RalA-dependent GLUT4 translocation in response to insulin in muscle cells. These findings show that GARNL1/RalGAP alpha 1 is the missing link that connects the insulin-PKB/Akt signaling pathway with the activation of the RalA small GTPase in muscle cells. GARNL1/RalGAP alpha 1 and its phosphorylation and/or binding to 14-3-3s are critical for GLUT4 trafficking through RalA in muscle cells. (C) 2014 Elsevier Inc. All rights reserved.