Regulation of the SNARE-interacting protein Munc18c tyrosine phosphorylation in adipocytes by protein-tyrosine phosphatase 1B.
BACKGROUND
Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and adiposity and is a drug target for the treatment of obesity and diabetes. The molecular mechanisms underlying PTP1B metabolic actions require additional investigation.


RESULTS
Herein, we identify Munc18c as a novel PTP1B substrate in adipocytes and in vivo. We demonstrate nutritional regulation of Munc18c in adipose tissue revealing decreased expression upon high fat feeding. In addition, PTP1B deficiency leads to elevated Munc18c tyrosine phosphorylation and dissociation from syntaxin4. At the molecular level, we identify Munc18c Tyr218/219 and Tyr521 as key residues that mediate Munc18c interaction with PTP1B. Further, we uncover an essential role of Munc18c total tyrosine phosphorylation in general, and Tyr218/219 and Tyr521 in particular, in regulating its interactions and glucose uptake in adipocytes.


CONCLUSIONS
In conclusion, our findings identify PTP1B as the first known tyrosine phosphatase for Munc18c and a regulator of its phosphorylation and function in adipocytes.
Nutrition Department, University of California Davis, One Shields Ave, 3135 Meyer Hall, Davis, CA 95616, USA.
Jesse
J
Bakke
Ahmed
A
Bettaieb
Naoto
N
Nagata
Kosuke
K
Matsuo
Fawaz G
FG
Haj
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051938:Munc18 Proteins / Q000378:metabolism*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D051938:Munc18 Proteins; D050600:SNARE Proteins; D014443:Tyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse