title: Two distinct signalling cascades target the NF-kappaB regulatory factor c-IAP1 for degradation.
abstract: c-IAP1 (cellular inhibitor of apoptosis 1) has recently emerged as a negative regulator of the non-canonical NF-kappaB (nuclear factor kappaB) signalling cascade. Whereas synthetic IAP inhibitors have been shown to trigger the autoubiquitination and degradation of c-IAP1, less is known about the physiological mechanisms by which c-IAP1 stability is regulated. In the present paper, we describe two distinct cellular processes that lead to the targeted loss of c-IAP1. Recruitment of a TRAF2 (tumour necrosis factor receptor-associated factor 2)-c-IAP1 complex to the cytoplasmic domain of the Hodgkin's/anaplastic large-cell lymphoma-associated receptor, CD30, leads to the targeting and degradation of the TRAF2-c-IAP1 heterodimer through a mechanism requiring the RING (really interesting new gene) domain of TRAF2, but not c-IAP1. In contrast, the induced autoubiquitination of c-IAP1 by IAP antagonists causes the selective loss of c-IAP1, but not TRAF2, thereby releasing TRAF2. Thus c-IAP1 can be targeted for degradation by two distinct processes, revealing the critical importance of this molecule as a regulator of numerous intracellular signalling cascades.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Csomos
authors.forename: Casey W
authors.initials: CW
authors.lastname: Wright
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Karolyn A
authors.initials: KA
authors.lastname: Oetjen
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
mesh_terms: D002460:Cell Line; D003593:Cytoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D017730:Ki-1 Antigen / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D017730:Ki-1 Antigen; D046912:Multiprotein Complexes; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2