The common cytokine receptor gamma(c) is shared by the interleukin-2, -4, -7, -9 - 15, and -21 receptors, and is essential for lymphocyte proliferation and survival. The regulation of y(c) receptor expression level is therefore critical for the ability of cells to respond to these cytokines. We previously reported that yc is efficiently constitutively internalized and addressed towards a degradation endocytic compartment. We show that gamma(c) is ubiquitinated and also associated to ubiquitinated proteins. We report that the ubiquitin-ligase c-Cbl induces gamma(c) down-regulation. In addition, the ubiquitin-hydrolase, DUB-2, counteracts the effect of c-Cbl on gamma(c) expression. We show that an increase in DUB-2 expression correlates with an increased yc half-life, resulting in the up-regulation of the receptor. Altogether, we show that yc is the target of an ubiquitination mechanism and its expression level can be regulated through the activities of a couple of ubiquitin-ligase/ubiquitin-hydrolase enzymes, namely c-Cbl/DUB-2. (c) 2005 Elsevier Inc. All rights reserved.