Controlling receptor downregulation by ubiquitination and deubiquitination.

Growth factor-activated receptor tyrosine kinases (RTKs) undergo rapid endocytosis and degradation in lysosomes. This process, known as receptor downregulation, is essential to prevent the overgrowth of cells by terminating signal transduction from activated RTKs. Thus, defects in RTK downergulation lead to cell proliferative disorders such as cancer. Upon endocytosis, RTKs are delivered to endosomes, from where they are further transported to lysosomes. Ubiquitin serves as a sorting signal that is tagged on activated RTKs and directs their trafficking from endosomes to lysosomes. On the endosomal membrane, ubiquitinated RTKs are sorted by coordinated actions of the class E vacuolar protein sorting (Vps) proteins some of which form complexes that directly recognize the ubiquitin moieties of RTKs. UBPY and AMSH in mammals, as well as Doa4 in yeast, are deubiquitinating enzymes (DUBs) that associate with class E Vps proteins on endosomes. Here I review the recently unveiled roles and regulatory mechanisms of these DUBs in the endosomal sorting of ubiquitinated cargo proteins. These findings suggest that RTK downregulation is controlled not only by ubiquitination but also by deubiquitination of RTKs as well as other endosomal proteins. Therefore, elucidating the entire functions and regulation of the endosomal DUBs potentially provides novel molecular targets for the treatment of cancer accompanied by overexpression or constitutive activation of RTKs.