title: Inhibition of the protein tyrosine phosphatase SHP-1 increases glucose uptake in skeletal muscle cells by augmenting insulin receptor signaling and GLUT4 expression.
abstract: The protein tyrosine phosphatase (PTPase) Src-homology 2-domain-containing phosphatase (SHP)-1 was recently reported to be a novel regulator of insulin's metabolic action. In order to examine the role of this PTPase in skeletal muscle, we used adenovirus (AdV)-mediated gene transfer to express an interfering mutant of SHP-1 [dominant negative (DN)SHP-1; mutation C453S] in L6 myocytes. Expression of DNSHP-1 increased insulin-induced Akt serine-threonine kinase phosphorylation and augmented glucose uptake and glycogen synthesis. Pharmacological inhibition of glucose transporter type 4 (GLUT4) activity using indinavir and GLUT4 translocation assays revealed an important role for this transporter in the increased insulin-induced glucose uptake in DNSHP-1-expressing myocytes. Both GLUT4 mRNA and protein expression were also found to be increased by DNSHP-1 expression. Furthermore, AdV-mediated delivery of DNSHP-1 in skeletal muscle of transgenic mice overexpressing Coxsackie and AdV receptor also enhanced GLUT4 protein expression. Together, these findings confirm that SHP-1 regulates muscle insulin action in a cell-autonomous manner and further suggest that the PTPase negatively modulates insulin action through down-regulation of both insulin signaling to Akt and GLUT4 translocation, as well as GLUT4 expression.
authors.affiliation: Department of Medicine, Faculty of Medicine, Cardiology Axis of Quebec Heart and Lung Institute, Ste-Foy, Québec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bergeron
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Dubois
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bellmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwab
authors.forename: Nancy
authors.initials: N
authors.lastname: Larochelle
authors.forename: Joséphine
authors.initials: J
authors.lastname: Nalbantoglu
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051275:Glucose Transporter Type 4; D006003:Glycogen; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D005947:Glucose