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Published online before print January 16, 2007

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(Journal of Leukocyte Biology. 2007;81:1137-1148.)
© 2007 by Society for Leukocyte Biology

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

¹ Correspondence: Baylor College of Medicine, One Baylor Plaza, BCM 285, Houston, TX 77030-3411, USA. E-mail: mxm{at}bcm.tmc.edu

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, ßc. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the ßc-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 ßc ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the ßc cytoplasmic domain and identify lysine residues 566 and 603 as sites of ßc ubiquitination. Lastly, we show that ubiquitination of the ßc 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 ßc tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the ßc 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 • ßc-sharing receptors • hematopoietic cytokines • eosinophils

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