Ubiquitination is a versatile post-translational modification that regulates a large number of different cellular processes including signal transduction, protein trafficking, DNA repair, gene transcription and regulated protein degradation. Typically, ubiquitin is appended to a target protein as a signal that is then received and interpreted by proteins carrying ubiquitin-binding domains (UBDs). UBDs are numerous and diverse, and, in most cases, little is known about how they function in the physiological context of a full-length protein. Several protein interaction SH3 domains were recently discovered to act as UBDs, whereas SH3 domains were previously thought to act almost exclusively by recognizing proline-rich peptides. The known ubiquitin-binding SH3 domains are components of the endocytic machinery. The first-discovered and perhaps best-characterized role of ubiquitin outside proteasome degradation is as a regulator of receptor endocytosis. Numerous components of the endocytic machinery that act to internalize cargo are ubiquitinated and/or carry UBDs. Furthermore, many endocytic cargo proteins are themselves modified by ubiquitin at the plasma membrane, where ubiquitin acts as a regulated internalization signal to direct these proteins into endocytic vesicles. Specific cargo proteins that are ubiquitinated and regulated by ubiquitin-dependent endocytosis include leptin receptors, growth factor receptors, glucose transporters, ion channels, the aquaporin-2 water channel and the anthrax toxin receptor. Impairment of ubiquitin-dependent endocytosis results in, or is linked to, diseases including hypertension, cancers, immune disorders and viral infections, as well as inflammation and bacterial toxin entry into cells. Three components of the endocytic machinery that bind to ubiquitin through SH3 domains have been identified: amphiphysin, CIN85 and the yeast homologue of CIN85, SlA1. Biochemical and genetic experiments proposed in this grant will define the function of ubiquitin in regulating these proteins, and will provide a general paradigm for how ubiquitin regulates the formation of the protein-protein interactions mediated by SH3 domains.
The research in this grant is proposed to define how plasma membrane proteins are regulated by removal from the cell surface by endocytosis. The small protein ubiquitin plays an important role in this process and disruption of ubiquitin-dependent endocytosis results in or is linked to many diseases, including hypertension, inflammation, immune diseases, multiple cancers, viral infections and bacterial toxin entry into cells. Endocytosis regulated by ubiquitin is also essential for developmental processes in complex organisms, such as cell fate specification and development of the nervous system.
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