HMG-I(Y) PHOSPHORYLATION STATUS AS A NUCLEAR TARGET REGULATED THROUGHINSULIN-RECEPTOR SUBSTRATE-1 AND THE I4R MOTIF OF THE INTERLEUKIN-4 RECEPTOR

Interleukin (IL)-4 is a cytokine that regulates both the growth and di fferentiation of hematopoietic cells. Its ligand binding specificity a nd important signal transduction mechanisms are conferred by the IL-4 receptor alpha chain (IL-4R alpha). The I4R is a tyrosine containing m otif within IL-4R alpha that is critical for proliferative responses t o IL-4. Although the I4R also contributes to gene regulation, nuclear targets directly regulated by this motif have not been described, It i s shown here that the tyrosine at position 497 in the I4R is critical for regulation of the phosphorylation status of a set of nuclear prote ins that includes HMG-I(Y), small non-histone chromosomal proteins inv olved in the control of gene expression in hematopoietic cell lines. M oreover, IL-4 is unable to induce HMG-I(Y) phosphorylation in insulin receptor substrate-1-deficient cells, and the inhibitor wortmannin com pletely blocks IL-4 regulation of HMG-I(Y) phosphorylation status but not activation of an IL-4 Stat protein. Taken together, these data ind icate that HMG-I(Y) is a nuclear target whose phosphorylation status i s regulated through the I4R motif via insulin receptor substrate prote ins, independent of activation of the Stat pathway.