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Involvement of the Ubiquitin-Proteasome Pathway in the Degradation of Nontyrosine Kinase-Type Cytokine Receptors of IL-9, IL-2, and Erythropoietin¹

Chao-Huang Yen^*, Yu-Chung Yang, Sandra K. Ruscetti, Robert A. Kirken, Ren Ming Dai^* and Chou-Chi H. Li^2,*

^* Intramural Research Support Program, Science Application International Corp.-Frederick, and Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; Department of Medicine and Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; and Department of Integrative Biology and Pharmacology, University of Texas, Houston, TX 77030

The ubiquitin-dependent proteasome-mediated (Ub-Pr) degradation pathway has been shown to regulate a large variety of substrates, including nuclear, cytosolic, and membrane proteins. In mammalian systems, polyubiquitin modification has been identified in a number of cell surface receptors for more than a decade; however, its biological significance has remained unclear until recently. For growth factor receptors with intrinsic tyrosine kinase domains, polyubiquitination is believed to trigger the internalization and subsequent degradation via the lysosomal pathway. In this study we provide the first evidence that non-tyrosine kinase-type cytokine surface receptors, IL-9R -chain, IL-2 receptor -chain, and erythropoietin receptor, can be polyubiquitinated and degraded by proteasomes. The Ub-Pr pathway regulates both the basal level turnover and the ligand-induced degradation of the receptors. A previously identified putative molecular chaperon, valosin-containing protein, undergoes tyrosine phosphorylation in a cytokine-dependent manner and associates with the receptor complexes following receptor engagement, suggesting that valosin-containing protein may target the ubiquitinated receptors to the proteasome for degradation.

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