title: Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.
abstract: How the Sec1/Munc18-syntaxin complex might transition to form the SNARE core complex remains unclear. Toward this, Munc18c tyrosine phosphorylation has been correlated with its dissociation from syntaxin 4. Using 3T3-L1 adipocytes subjected to small interfering ribonucleic acid reduction of Munc18c as a model of impaired insulin-stimulated GLUT4 vesicle exocytosis, we found that coordinate expression of Munc18c-wild type or select phosphomimetic Munc18c mutants, but not phosphodefective mutants, restored GLUT4 vesicle exocytosis, suggesting a requirement for Munc18c tyrosine phosphorylation at Tyr219 and Tyr521. Surprisingly, the insulin receptor (IR) tyrosine kinase was found to target Munc18c at Tyr521 in vitro, rapidly binding and phosphorylating endogenous Munc18c within adipocytes and skeletal muscle. IR, but not phosphatidylinositol 3-kinase, activation was required. Altogether, we identify IR as the first known tyrosine kinase for Munc18c as part of a new insulin-signaling step in GLUT4 vesicle exocytosis, exemplifying a new model for the coordination of SNARE assembly and vesicle mobilization events in response to a single extracellular stimulus.
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Jenna L
authors: JL
authors: Jewell
authors: Eunjin
authors: E
authors: Oh
authors: Latha
authors: L
authors: Ramalingam
authors: Michael A
authors: MA
authors: Kalwat
authors: Vincent S
authors: VS
authors: Tagliabracci
authors: Lixuan
authors: L
authors: Tackett
authors: Jeffrey S
authors: JS
authors: Elmendorf
authors: Debbie C
authors: DC
authors: Thurmond
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D004330:Drosophila; D005089:Exocytosis; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D051938:Munc18 Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction
chemical_list: D051938:Munc18 Proteins; D050600:SNARE Proteins; D011972:Receptor, Insulin