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Published online before print January 16, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0706465

Received for publication July 21, 2006.
Revised November 14, 2006.
Accepted for publication December 11, 2006.

Article

JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

Biology of Inflammation Center and Immunology, Allergy and Rheumatology Section, Departments of Medicine and Immunology, Baylor College of Medicine, Houston, Texas, USA

^@ To whom correspondence should be addressed. E-mail: mxm{at}bcm.tmc.edu.

	Abstract

IL-5, IL-3, and GM-CSF are related hematopoietic cytokines, which regulate the function of myeloid cells and are mediators of the allergic inflammatory response. These cytokines signal through heteromeric receptors containing a specific chain and a shared signaling chain, c. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the c-sharing receptors. In this study, the upstream molecular events leading to proteasome degradation of the IL-5 receptor (IL-5R) were examined. By using biochemical and flow cytometric methods, we show that JAK kinase activity is required for c ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the c cytoplasmic domain and identify lysine residues 566 and 603 as sites of c ubiquitination. Lastly, we show that ubiquitination of the c cytoplasmic domain begins at the plasma membrane, increases after receptor internalization, and is degraded by the proteasome after IL-5R internalization. We propose an updated working model of IL-5R down-regulation, whereby IL-5 ligation of its receptor activates JAK2/1 kinases, resulting in c tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the c cytoplasmic domain, and the truncated receptor complex is terminally degraded in the lysosomes. These data establish a critical role for JAK kinases and the Ub/proteasome degradation pathway in IL-5R down-regulation.

Key Words: signal transduction • endocytosis • c-sharing receptors • hematopoietic cytokines • eosinophils

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