Sakamoto Kei, Holman Geoffrey D
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow St., Dundee, DD1 5EH, UK.
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E29-37. doi: 10.1152/ajpendo.90331.2008. Epub 2008 May 13.
Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.
葡萄糖转运蛋白GLUT4的囊泡运输是对胰岛素、肌肉收缩和导致细胞能量状态变化的代谢刺激的响应。这些刺激与相关的激酶级联反应有关，激酶级联反应导致葡萄糖摄取的变化，以应对胰岛素反应性组织中高度调节的细胞类型所面临的能量挑战。长期以来，人们一直知道需要从机制上将这些与激酶相关的刺激与囊泡运输中可识别的中间体联系起来，但这一直难以实现。Rab鸟苷三磷酸酶激活蛋白AS160和TBC1D1现已成为填补这一空白的有力候选者。在此，我们回顾了这些蛋白最初作为Akt磷酸化底物的发现，以及最近出现的数据，这些数据表明这些蛋白是收缩和能量状态信号下游其他激酶的底物。将这些磷酸化蛋白与囊泡运输偶联的机制似乎依赖于与Rab家族的小GTP酶的连接。我们研究了一种假说的现状，该假说认为Rab鸟苷三磷酸酶激活蛋白的磷酸化导致Rab蛋白在GLUT4囊泡上的GTP负载增加，随后与控制GLUT4囊泡转运的Rab效应器的相互作用增加。
