Tyrosine phosphorylation of Munc18c regulates platelet-derived growth factor-stimulated glucose transporter 4 translocation in 3T3L1 adipocytes.
Platelet-derived growth factor (PDGF) stimulation of skeletal muscle, cultured myotubes, and 3T3L1 adipocytes results in glucose transporter 4 (Glut4) translocation, albeit to a reduced level compared with insulin. To address the mechanism of PDGF action, we have determined that the Syntaxin 4 negative regulatory protein, Munc18c, undergoes PDGF-stimulated phosphorylation on tyrosine residue 521. The tyrosine phosphorylation of Munc18c on Y521 occurred concomitant with the dissociation of the Munc18c protein from Syntaxin 4 in a time frame consistent with Glut4 translocation. Moreover, expression of the wild-type Munc18c protein did not inhibit PDGF-induced Glut4 translocation, whereas expression of Y521A-Munc18c mutant was inhibitory and failed to dissociate from Syntaxin 4. In contrast, expression of either wild-type Munc18c or the Y521A-Munc18c mutant both resulted in a marked inhibition of insulin-stimulated Glut4 translocation. Together, these data demonstrate that one mechanism accounting for the PDGF induction of Glut4 translocation is the suppression of the Munc18c negative regulation of Syntaxin 4 function.
Umahara
Mitsuhiko
M
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Okada
Shuichi
S
Yamada
Eijiro
E
Saito
Tsugumichi
T
Ohshima
Kihachi
K
Hashimoto
Koshi
K
Yamada
Masanobu
M
Shimizu
Hiroyuki
H
Pessin
Jeffrey E
JE
Mori
Masatomo
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D051938:Munc18 Proteins / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D051275:Glucose Transporter Type 4; D007328:Insulin; D051938:Munc18 Proteins; D010982:Platelet-Derived Growth Factor; D050765:Qa-SNARE Proteins; C495693:Slc2a4 protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases