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J. Biol. Chem., Vol. 277, Issue 27, 24306-24314, July 5, 2002

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Glucose Regulates Insulin Mitogenic Effect by Modulating SHP-2 Activation and Localization in JAr Cells^*

Giuseppe Bifulco^§, Costantino Di Carlo, Matilde Caruso^¶, Francesco Oriente^¶, Attilio Di Spiezio Sardo, Pietro Formisano^¶, Francesco Beguinot^¶, and Carmine Nappi

From the  Dipartimento di Ginecologia, Ostetricia e Fisiopatologia della Riproduzione Umana and the ^¶ Dipartimento di Biologia e Patologia Molecolare e Cellulare "L. Califano," Università degli Studi di Napoli "Federico II," 80131 Naples, Italy

The glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6 mM glucose (LG), proliferation and thymidine incorporation were induced by serum, epidermal growth factor, and insulin-like growth factor 1 but not by insulin. In contrast, at 25 mM glucose (HG), proliferation and thymidine incorporation were stimulated by insulin, serum, epidermal growth factor, and insulin-like growth factor 1 to a comparable extent, whereas basal levels were 25% lower than those in LG. HG culturing also enhanced insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine phosphorylations while decreasing basal phosphorylations. These actions of glucose were accompanied by an increase in cellular tyrosine phosphatase activity. The activity of SHP-2 in HG-treated JAr cells was 400% of that measured in LG-treated cells. SHP-2 co-precipitation with IRS1 was also increased in HG-treated cells. SHP-2 was mainly cytosolic in LG-treated cells. However, HG culturing largely redistributed SHP-2 to the internal membrane compartment, where tyrosine-phosphorylated IRS1 predominantly localizes. Further exposure to insulin rescued SHP-2 cytosolic localization, thereby preventing its interaction with IRS1. Antisense inhibition of SHP-2 reverted the effect of HG on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation as well as that on thymidine incorporation. Thus, in JAr cells, glucose modulates insulin mitogenic action by modulating SHP-2 activity and intracellular localization.

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