Signaling-mediated control of ubiquitin ligases in endocytosis

Ubiquitination modifies proteins in a variety of ways, the significance of which we only partially comprehend. Ubiquitin can be attached: as an individual moiety to a single or multiple lysine residues of substrate (mono- or multiple monoubiquitination); as chains of ubiquitin moieties that are interlinked through any one of the seven lysine residues of ubiquitin (for example K48- or K63-linked chains); or as branched chains, to name but a few [1]. The cell interprets each of these modifications as a distinct signal. The first described role of ubiquitination as mediating protein degradation through targeting to the proteasome has now been complemented with numerous other functions [2]. For example, the signal encoded by K63-linked chains can mediate functions as diverse as receptor endocytosis [3,4], activation of protein kinases in the NF-κB pathway and the initiation of error-free DNA repair [2].Signal transduction from transmembrane cell surface receptors to nuclear transcription factors is regulated at multiple levels by protein ubiquitination. The covalent attachment of one, or often more, ubiquitin moieties has emerged as the principal mechanism for termination of signaling, by targeting the receptor for endocytosis and, ultimately, degradation in the lysosome [3]. This device controls a vast array of mammalian signaling receptors, such as receptor tyrosine kinases, G-protein coupled receptors (GPCRs), growth hormone receptors, the major histocompatibility complex I, NOTCH, various channels and transporters, and cytokine and interferon receptors [3]. Receptors that are internalized after activation are directed first into the endosomes of the endocytic pathway, and then into multivesicular bodies (MVBs), which undergo a process of maturation that ends with fusion with the lysosome and delivery of the contents for degradation. Ubiquitination of the receptor provides the crucial signal for entering this pathway [3,5-7].Subsequent delivery of membrane receptors