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 language | English |
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Pages (from-to) | 1636-1648 |
Number of pages | 13 |
Journal | Cellular Signalling |
Volume | 26 |
Issue number | 8 |
Early online date | 24 Apr 2014 |
DOIs | |
Publication status | Published - 2014 |
Keywords
- Insulin signaling
- GLUT4 trafficking
- GARNL1/RalGAPα1
- Protein phosphorylation
- 14-3-3 interaction