HMG-I(Y) phosphorylation status as a nuclear target regulated through insulin receptor substrate-1 and the I4R motif of the interleukin-4 receptor.
Interleukin (IL)-4 is a cytokine that regulates both the growth and differentiation of hematopoietic cells. Its ligand binding specificity and important signal transduction mechanisms are conferred by the IL-4 receptor alpha chain (IL-4Ralpha). The I4R is a tyrosine-containing motif within IL-4Ralpha that is critical for proliferative responses to IL-4. Although the I4R also contributes to gene regulation, nuclear targets directly regulated by this motif have not been described. It is shown here that the tyrosine at position 497 in the I4R is critical for regulation of the phosphorylation status of a set of nuclear proteins that includes HMG-I(Y), small non-histone chromosomal proteins involved in the control of gene expression in hematopoietic cell lines. Moreover, IL-4 is unable to induce HMG-I(Y) phosphorylation in insulin receptor substrate-1-deficient cells, and the inhibitor wortmannin completely blocks IL-4 regulation of HMG-I(Y) phosphorylation status but not activation of an IL-4 Stat protein. Taken together, these data indicate that HMG-I(Y) is a nuclear target whose phosphorylation status is regulated through the I4R motif via insulin receptor substrate proteins, independent of activation of the Stat pathway.
Wang
D
D
Department of Microbiology & Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232-2363, USA.
Zamorano
J
J
Keegan
A D
AD
Boothby
M
M
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025741:HMGA1a Protein; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D051381:Rats; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis; D014162:Transfection; D014443:Tyrosine; D000077191:Wortmannin
D000730:Androstadienes; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D006609:High Mobility Group Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D046911:Macromolecular Substances; D010750:Phosphoproteins; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D025741:HMGA1a Protein; D014443:Tyrosine; D000077191:Wortmannin