Identification of P-Rex1 as a Novel Rac1-Guanine Nucleotide Exchange Factor (GEF) That Promotes Actin Remodeling and GLUT4 Protein Trafficking in Adipocytes
Identification of P-Rex1 as a Novel Rac1-Guanine Nucleotide Exchange Factor (GEF) That Promotes Actin Remodeling and GLUT4 Protein Trafficking in Adipocytes
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DOI：
10.1074/jbc.m111.306621
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发表时间：
2011-12-16
影响因子：
4.8
通讯作者：
Mitchell, Christina A.
中科院分区：
文献类型：
--
作者：
Balamatsias, Demis;Kong, Anne M.;Mitchell, Christina A.
磷酸肌醇3-激酶（PI 3 K）信号转导促进葡萄糖转运蛋白GLUT 4易位至胰岛素敏感组织的质膜，以促进葡萄糖摄取。在脂肪细胞中，胰岛素刺激的肌动蛋白细胞骨架重组已被提出以PI 3 K依赖性方式在促进GLUT 4易位和葡萄糖摄取中发挥作用。然而，通过调节脂肪细胞中的肌动蛋白细胞骨架来促进GLUT 4易位的PI 3 K效应器仍有待充分阐明。在这里，我们证明了PI 3 K依赖的Rac交换因子，P-Rex 1，增强膜皱褶在3 T3-L1脂肪细胞，并促进GLUT 4运输到质膜在次最大的胰岛素浓度。P-Rex 1促进的GLUT 4运输需要功能性肌动蛋白网络和膜皱褶形成，并以PI 3 K和Rac 1依赖的方式发生。相反，其他Rho GTP酶，如Cdc 42或Rho的表达，不影响胰岛素刺激的P-Rex 1介导的GLUT 4运输。P-Rex 1 siRNA敲除或P-Rex 1显性阴性突变体的表达降低，但不能完全抑制响应胰岛素的葡萄糖摄取。总的来说，这些研究确定了一种新的RacGEF在脂肪细胞中作为P-Rex 1，在生理胰岛素浓度下，作为肌动蛋白细胞骨架的胰岛素依赖性调节剂，有助于GLUT 4运输到质膜。
Phosphoinositide 3-kinase (PI3K) signaling promotes the translocation of the glucose transporter, GLUT4, to the plasma membrane in insulin-sensitive tissues to facilitate glucose uptake. In adipocytes, insulin-stimulated reorganization of the actin cytoskeleton has been proposed to play a role in promoting GLUT4 translocation and glucose uptake, in a PI3K-dependent manner. However, the PI3K effectors that promote GLUT4 translocation via regulation of the actin cytoskeleton in adipocytes remain to be fully elucidated. Here we demonstrate that the PI3K-dependent Rac exchange factor, P-Rex1, enhances membrane ruffling in 3T3-L1 adipocytes and promotes GLUT4 trafficking to the plasma membrane at submaximal insulin concentrations. P-Rex1-facilitated GLUT4 trafficking requires a functional actin network and membrane ruffle formation and occurs in a PI3K- and Rac1-dependent manner. In contrast, expression of other Rho GTPases, such as Cdc42 or Rho, did not affect insulin-stimulated P-Rex1-mediated GLUT4 trafficking. P-Rex1 siRNA knockdown or expression of a P-Rex1 dominant negative mutant reduced but did not completely inhibit glucose uptake in response to insulin. Collectively, these studies identify a novel RacGEF in adipocytes as P-Rex1 that, at physiological insulin concentrations, functions as an insulin-dependent regulator of the actin cytoskeleton that contributes to GLUT4 trafficking to the plasma membrane.