title: RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase.
abstract: Through specific interactions with members of the tumor necrosis receptor (TNFR) family, adapter molecules such as the serine/threonine (Ser/Thr) kinase RIP mediate divergent signaling pathways including NF-kappaB activation and cell death. In this study, we have identified and characterized a novel 61-kDa protein kinase related to RIP that is a component of both the TNFR-1 and the CD40 signaling complexes. Receptor interacting protein-2 (RIP2) contains an N-terminal domain with homology to Ser/Thr kinases and a C-terminal caspase activation and recruitment domain (CARD), a homophilic interaction motif that mediates the recruitment of caspase death proteases. Overexpression of RIP2 signaled both NF-kappaB activation and cell death. Mutational analysis revealed the pro-apoptotic function of RIP2 to be restricted to its C-terminal CARD domain, whereas the intact molecule was necessary for NF-kappaB activation. RIP2 interacted with other members of the TNFR-1 signaling complex, including inhibitor of apoptosis protein cIAP1 and with members of the TNFR-associated factor (TRAF) family, specifically TRAF1, TRAF5, and TRAF6, but not with TRAF2, TRAF3, or TRAF4. These TRAF interactions mediate the recruitment of RIP2 to receptor signaling complexes.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: McCarthy
authors.forename: J
authors.initials: J
authors.lastname: Ni
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D003001:Cloning, Molecular; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010770:Phosphotransferases / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; C494833:BIRC2 protein, human; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse