Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in L6 myocytes and Fao hepatoma cells

Insulin signaling is regulated by tyrosine phosphorylation of the signaling molecules, such as the insulin receptor and insulin receptor substrates (I RSs), Therefore, the balance between protein-tyrosine kinases and protein-t yrosine phosphatase activities is thought to be important in the modulation of insulin signaling in insulin-resistant states. We thus employed the ade novirus-mediated gene transfer technique, and we analyzed the effect of ove rexpression of a wild-type protein-tyrosine phosphatase-1B (PTP1B) on insul in signaling in both L6 myocytes and Fao cells. In both cells, PTP1B overex pression blocked insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 by more than 70% and resulted in a significant inhibiti on of the association between IRS-1 and the p85 subunit of phosphatidylinos itol 3-kinase and Akt phosphorylation as well as mitogen-activated protein kinase phosphorylation, Moreover, insulin-stimulated glycogen synthesis was also inhibited by PTP1B overexpression in both cells. These effects were s pecific for insulin signaling, because platelet-derived growth factor (PDGF )-stimulated PDGF receptor tyrosine phosphorylation and Akt phosphorylation were not inhibited by PTP1B overexpression. The present findings demonstra te that PTP1B negatively regulates insulin signaling in L6 and Fao cells, s uggesting that PTP1B plays an important role in insulin resistance in muscl e and liver.