| First Author | Uhm M | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 471 | PubMed ID | 28325821 |
| Mgi Jnum | J:260011 | Mgi Id | MGI:6141728 |
| Doi | 10.1126/scisignal.aah5085 | Citation | Uhm M, et al. (2017) Phosphorylation of the exocyst protein Exo84 by TBK1 promotes insulin-stimulated GLUT4 trafficking. Sci Signal 10(471) |
| abstractText | Insulin stimulates glucose uptake through the translocation of the glucose transporter GLUT4 to the plasma membrane. The exocyst complex tethers GLUT4-containing vesicles to the plasma membrane, a process that requires the binding of the G protein (heterotrimeric guanine nucleotide-binding protein) RalA to the exocyst complex. We report that upon activation of RalA, the protein kinase TBK1 phosphorylated the exocyst subunit Exo84. Knockdown of TBK1 blocked insulin-stimulated glucose uptake and GLUT4 translocation; knockout of TBK1 in adipocytes blocked insulin-stimulated glucose uptake; and ectopic overexpression of a kinase-inactive mutant of TBK1 reduced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. The phosphorylation of Exo84 by TBK1 reduced its affinity for RalA and enabled its release from the exocyst. Overexpression of a kinase-inactive mutant of TBK1 blocked the dissociation of the TBK1/RalA/exocyst complex, and treatment of 3T3-L1 adipocytes with specific inhibitors of TBK1 reduced the rate of complex dissociation. Introduction of phosphorylation-mimicking or nonphosphorylatable mutant forms of Exo84 blocked insulin-stimulated GLUT4 translocation. Thus, these data indicate that TBK1 controls GLUT4 vesicle engagement and disengagement from the exocyst, suggesting that exocyst components not only constitute a tethering complex for the GLUT4 vesicle but also act as "gatekeepers" controlling vesicle fusion at the plasma membrane. |
