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-κB 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 interactingprotein-2 (RIP2) contains an N-terminal domain with homology to Ser/Thr kinases and a C-terminal caspaseactivation and recruitment domain (CARD), a homophilic interaction motif that mediates the recruitment of caspase death proteases. Overexpression of RIP2 signaled both NF-κB 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-κB 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.

The elimination of cells by programmed cell death is a fundamental even in developmental event in development where multicellular ogranisms regulate cell numbers or eliminate cells that are functional reduandant or potentially detrimental to the ogranism. The evolutionary conservation of the biochemical and genetic regulating of programmed cell death across species has allowed the genetic pathyways of programmed cell death determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Dorsophila melangaster to act as models to delineate the genetics and regulation of cell death in mammalian cells. These studies have identified cell autonomous and non‐autonomous mechanisms that regulate of cell death and reveal that developmental cell death can either be a pre‐determined cell fate or the consequence of insufficient cell interactions that normally promote cell survival.