Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
German Center for Diabetes Research (DZD), Düsseldorf, Germany.
Biochem Soc Trans. 2018 Jun 19;46(3):683-690. doi: 10.1042/BST20170479. Epub 2018 May 21.
Rab (Ras-related proteins in brain) GTPases are key proteins responsible for a multiplicity of cellular trafficking processes. Belonging to the family of monomeric GTPases, they are regulated by cycling between their active GTP-bound and inactive GDP-bound conformations. Despite possessing a slow intrinsic GTP hydrolysis activity, Rab proteins rely on RabGAPs (Rab GTPase-activating proteins) that catalyze GTP hydrolysis and consequently inactivate the respective Rab GTPases. Two related RabGAPs, TBC1D1 and TBC1D4 (=AS160) have been described to be associated with obesity-related traits and type 2 diabetes in both mice and humans. Inactivating mutations of and lead to substantial changes in trafficking and subcellular distribution of the insulin-responsive glucose transporter GLUT4, and to subsequent alterations in energy substrate metabolism. The activity of the RabGAPs is controlled through complex phosphorylation events mediated by protein kinases including AKT and AMPK, and by putative regulatory interaction partners. However, the dynamics and downstream events following phosphorylation are not well understood. This review focuses on the specific role and regulation of TBC1D1 and TBC1D4 in insulin action.
Rab（大脑中的 Ras 相关蛋白）GTPases 是负责多种细胞运输过程的关键蛋白。它们属于单体 GTPases 家族，通过其活性 GTP 结合和非活性 GDP 结合构象之间的循环来调节。尽管 Rab 蛋白具有缓慢的内在 GTP 水解活性，但它们依赖于 RabGAPs（Rab GTPase 激活蛋白）来催化 GTP 水解，从而使相应的 Rab GTPases 失活。两种相关的 RabGAPs，TBC1D1 和 TBC1D4（=AS160）已被描述为与肥胖相关特征和 2 型糖尿病在小鼠和人类中相关。 和 的失活突变导致胰岛素反应性葡萄糖转运体 GLUT4 的运输和亚细胞分布发生实质性变化，并随后导致能量底物代谢的改变。RabGAP 的活性通过包括 AKT 和 AMPK 在内的蛋白激酶介导的复杂磷酸化事件以及假定的调节性相互作用伙伴来控制。然而，磷酸化后的动力学和下游事件尚不清楚。这篇综述重点介绍了 TBC1D1 和 TBC1D4 在胰岛素作用中的特定作用和调节。
