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

Qiaoli Chen, Chao Quan, Bingxian Xie, Liang Chen, Shuilian Zhou, Rachel Toth, David G. Campbell, Shuangshuang Lu, Ryutaro Shirakawa, Hisanori Horiuchi, Chaojun Li, Zhongzhou Yang, Carol MacKintosh, Hong Yu Wang (Lead / Corresponding author), Shuai Chen (Lead / Corresponding author)

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1636-1648
Number of pages13
JournalCellular Signalling
Volume26
Issue number8
Early online date24 Apr 2014
DOIs
Publication statusPublished - 2014

Keywords

  • Insulin signaling
  • GLUT4 trafficking
  • GARNL1/RalGAPα1
  • Protein phosphorylation
  • 14-3-3 interaction

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