GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins

TY - JOUR

T1 - GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins

AU - Chen, Qiaoli

AU - Quan, Chao

AU - Xie, Bingxian

AU - Chen, Liang

AU - Zhou, Shuilian

AU - Toth, Rachel

AU - Campbell, David G.

AU - Lu, Shuangshuang

AU - Shirakawa, Ryutaro

AU - Horiuchi, Hisanori

AU - Li, Chaojun

AU - Yang, Zhongzhou

AU - MacKintosh, Carol

AU - Wang, Hong Yu

AU - Chen, Shuai

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2014

Y1 - 2014

N2 - 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/RalGAPa1, 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 Thr735 on GARNL1/RalGAPa1. Knockdown of GARNL1/RalGAPa1 increased, while overexpression of GARNL1/RalGAPa1Thr735Ala mutant protein decreased, the RalA activation and the RalA-dependent GLUT4 translocation in response to insulin in muscle cells. These findings show that GARNL1/RalGAPa1 is the missing link that connects the insulin-PKB/Akt signaling pathway with the activation of the RalA small GTPase in muscle cells. GARNL1/RalGAPa1 and its phosphorylation and/or binding to 14-3-3s are critical for GLUT4 trafficking through RalA in muscle cells.

AB - 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/RalGAPa1, 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 Thr735 on GARNL1/RalGAPa1. Knockdown of GARNL1/RalGAPa1 increased, while overexpression of GARNL1/RalGAPa1Thr735Ala mutant protein decreased, the RalA activation and the RalA-dependent GLUT4 translocation in response to insulin in muscle cells. These findings show that GARNL1/RalGAPa1 is the missing link that connects the insulin-PKB/Akt signaling pathway with the activation of the RalA small GTPase in muscle cells. GARNL1/RalGAPa1 and its phosphorylation and/or binding to 14-3-3s are critical for GLUT4 trafficking through RalA in muscle cells.

KW - Insulin signaling

KW - GLUT4 trafficking

KW - GARNL1/RalGAPα1

KW - Protein phosphorylation

KW - 14-3-3 interaction

U2 - 10.1016/j.cellsig.2014.04.012

DO - 10.1016/j.cellsig.2014.04.012

M3 - Article

C2 - 24768767

SN - 0898-6568

VL - 26

SP - 1636

EP - 1648

JO - Cellular Signalling

JF - Cellular Signalling

IS - 8

ER -