HIGH GLUCOSE-INDUCED ABNORMAL EPIDERMAL GROWTH-FACTOR SIGNALING

We have reported that high glucose conditions (27 mM for 4 days) induc es activation of protein tyrosine phosphatases (PTPases) which are ass ociated with impaired insulin signaling in Rat 1 fibroblasts expressin g human insulin receptors [Maegawa, H, et at. (1995) J, Biol, Chem, 27 0, 7724-7730], In this study, we found increased mRNA-levels of a non- receptor type PTPase, protein tyrosine phosphatase 1B (PTP1B), and rec eptor type PTPases, leukocyte common antigen-related phosphatase (LAR) , and LAR-related phosphatase (LRP), under high glucose conditions, In accordance with these results, LAR content was significantly increase d, whereas LRP content was not increased. Cytosolic PTP1B content was increased, but membrane-associated PTP1B content showed no detectable change. Pioglitazone, a thiazolidinedione, normalized increased cytoso lic PTPase activity through reduction of cytosolic PTP1B content, but it had no effect on mRNA levels of these PTPases, Under the high gluco se condition, we also found that epidermal growth factor (EGF)-stimula ted signaling, including tyrosine-phosphorylation of EGF receptor and phosphatidylinositol 3'-kinase activities, was attenuated. Nevertheles s, pioglitazone failed to restore the attenuated EGF-signaling. These results indicate that the high glucose conditions cause dysfunction of EGF receptor. However, the increased cytosolic PTP1B content is not i nvolved in the abnormal regulation of EGF-signaling, in contrast to in sulin-signaling.