title: Regulation of death receptor signaling by the ubiquitin system.
abstract: The study of death receptor (DR) signaling has led to the discovery of new signaling paradigms, including the first example of direct receptor-mediated activation of a protease (caspase-8) that functions as a second messenger to initiate a 'death cascade' of downstream protease activation. More recently, this receptor system has underscored the importance of ubiquitin modification in NF-kappaB activation. Both degradative lysine 48-linked polyubiquitin and scaffolding lysine 63-linked polyubiquitin have an essential role in signal propagation. Remarkably, a negative feedback process, termed ubiquitin editing, regulates signaling that emanates from certain DRs. Ubiquitin editing is mediated by a complex interplay between the ubiquitination and deubiquitination machinery, resulting in the replacement of signal enhancing lysine 63-linked polyubiquitin with signal extinguishing lysine 48-linked polyubiquitin. The ubiquitination machinery and its regulation in the context of DR signaling are discussed herein.
authors.affiliation: Department of Protein Engineering, Genentech Inc., South San Francisco, CA 94080, USA. ingrid@gene.com
authors.forename: I E
authors.initials: IE
authors.lastname: Wertz
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053468:CARD Signaling Adaptor Proteins; D053200:Fas-Associated Death Domain Protein; D053218:Receptors, Death Domain; D053199:TNF Receptor-Associated Death Domain Protein; D025801:Ubiquitin; D053181:Caspase 8