Critical proline residues of the cytoplasmic domain of the IL-5 receptor {alpha} chain and its function in IL-5-mediated activation of JAK kinase and STAT5 |
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Authors: | Kouro, Taku Kikuchi, Yuji Kanazawa, Hiroko Hirokawa, Katsuiku Harada, Nobuyuki Shiiba, Masashi Wakao, Hiroshi Takaki, Satoshi Takatsu, Kiyoshi |
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Affiliation: | Department of Immunology, Institute of Medical Science, University of Tokyo 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan 1 Department of Pathology, Tokyo Medical and Dental School Tokyo, Japan 2 DNAX Research Institute Palo Alto, CA 94304, USA |
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Abstract: | The high-affinity receptor (R) for IL-5 consists of a uniquea chain (IL-5Rc) and a ß chain (ßc) thatisshared with the receptors for IL-3 and granulocyte macrophagecolony stimulating factor (GM-CSF). We defined two regions ofIL-5R for the IL-5-induced proliferative response, the expressionof nuclear proto-oncogenes, and the tyrosine phosphorylationof cellular proteins including ßc, SH2/SH3-containingproteins and JAK2 kinase. In the studies described here, wedemonstrate that IL-5, IL-3 or GM-CSF stimulation induces thetyrosine phosphorylation of JAK2, and to a lesser extent JAK1,and of STAT5. Mutational analysis revealed that one of the prolineresidues, particularly Pro352and Pro355, in the membrane-proximalproline-rich sequence (Pro352-Pro353-X-Pro355) of the cytoplasmicdomain of IL-5R is required for cell proliferation, and forboth JAK1 and JAK2 activation. In addition, transfectants expressingchimeric receptors which consist of the extracellular domainof IL-5R and the cytoplasmic domain of ßc respondedtoIL-5 for proliferation and tyrosine phosphorylation of JAK1.Intriguingly, electrophoretic mobility shift assay analysisrevealed that STAT5 was activated in cells showing either JAK1or JAK2 tyrosine phosphorylation. These results indicate thatactivation of JAK1, JAK2 and STAT5 is critical to coupling IL-5-inducedtyrosine phosphorylation and ultimately mitogenesis, and thatPro352 and Pro355 in the proline-rich sequence appear to playmore essential roles in cell growth andin both JAK1/STAT5 andJAK2/STAT5 activation than Pro353 does. |
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Keywords: | IL-5 receptor /math/alpha.gif" ALT=" {alpha}" BORDER=" 0" > chain IL-5 signaling JAK2/STAT5 proline-rich motif |
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