Involvement of the ubiquitin-proteasome pathway in the degradation of nontyrosine kinase-type cytokine receptors of IL-9, IL-2, and erythropoietin

The ubiquitin-dependent proteasome-mediated (Ub-Pr) degradation pathway has been shown to regulate a large variety of substrates, including nuclear, c ytosolic, and membrane proteins. In mammalian systems, polyubiquitin modifi cation has been identified in a number of cell surface receptors for more t han a decade; however, its biological significance has remained unclear unt il recently, For growth factor receptors vith intrinsic tyrosine kinase dom ains, polyubiquitination is believed to trigger the internalization and sub sequent degradation via the lysosomal pathway, In this study we provide the first evidence that non-tyrosine kinase-type cytokine surface receptors, I L-9R alpha -chain, IL-2 receptor beta -chain, and erythropoietin receptor, can be polyubiquitinated and degraded by proteasomes. The Ub-Pr pathway reg ulates 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 depen dent manner and associates with the receptor complexes following receptor e ngagement, suggesting that valosin-containing protein may target the ubiqui tinated receptors to the proteasome for degradation.