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Developmental Expression of Insulin Receptor Substrate-2 During Dimethylsulfoxide-Induced Differentiation of Human HL-60 Cells¹

Daniel H. Schacher^*, Roger W. VanHoy^*, Qiang Liu^*,, Sean Arkins^*,§, Robert Dantzer^¶, Gregory G. Freund and Keith W. Kelley^2,*

^* Laboratory of Immunophysiology, Department of Animal Sciences, and College of Medicine, Department of Pathology, University of Illinois, Urbana, IL 61801; Department of Hematological Oncology, Cancer Center, Sun Yat-Sen University of Medical Science, Guangzhou, China; ^§ Department of Life Sciences, University of Limerick, Limerick, Ireland; and ^¶ Institut National de la Recherche Agronomique-Institut National de la Santé et de la Recherche Médicale, Unité de Recherches de Neurobiologie des Comportements, Bordeaux, France

Insulin receptor substrate-2 (IRS-2) is phosphorylated on tyrosine by a number of cytokine receptors and is implicated in the activation of phosphatidylinositol 3'-kinase (PI3-kinase). Here, we demonstrate that induction of granulocytic differentiation of human promyeloid HL-60 cells leads to an increase in the amount of IRS-2 that is phosphorylated in response to insulin-like growth factor (IGF)-I. Although PI3-kinase is often activated following interaction with IRS-1, we could not detect IRS-1 protein, IRS-1 mRNA, or IRS-1-precipitable PI3-kinase enzymatic activity. However, PI3-kinase activity that was coimmunoprecipitated with either anti-phosphotyrosine or anti-IRS-2 following IGF-I stimulation was increased 100-fold. Heightened tyrosine phosphorylation of IRS-2 during granulocytic differentiation was not caused by an increase in expression of the tyrosine kinase IGF-I receptor, as measured by the amount of both the - and ß-subunits. Instead, immunoblotting experiments with an Ab to IRS-2 revealed that induction of granulocytic differentiation caused a large increase in IRS-2, and this occurred in the absence of detectable IRS-1 protein. These IRS-2-positive cells could not differentiate into more mature myeloid cells in serum-free medium unless IGF-I was added. These data are consistent with a model of granulocytic differentiation that requires at least two signals, the first of which leads to an increase in the cytoplasmic pool of IRS-2 protein and a second molecule that acts to tyrosine phosphorylate IRS-2 and enhance granulocytic differentiation.

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