The receptor-interacting protein family of serine-threonine kinases are important regulators of cellular stress that trigger pro-survival and inflammatory responses through the activation of NF-κB, as well as pro-apoptotic pathways. In addition to the kinase domain, RIP contains a death domain responsible for interaction with the death domain receptor Fas and recruitment to TNF-R1 through interaction with TRADD. RIP-deficient cells show a failure in TNF-mediated NF-κB activation, making the cells more sensitive to apoptosis. RIP also interacts with TNF-receptor-associated factors and can recruit IKKs to the TNF-R1 signaling complex via interaction with NEMO, leading to IκB phosphorylation and degradation. Overexpression of RIP induces both NF-κB activation and apoptosis. Caspase-8-dependent cleavage of the RIP death domain can trigger the apoptotic activity of RIP.Receptor-interacting protein 3 was originally found to interact with RIP and the TNF receptor complex to induce apoptosis and activation of NF-κB. It has subsequently been shown that the association between RIP and RIP3 is a key component of a signaling pathway that results in programmed necrosis, a necrotic-like cell death induced by TNF in the presence of caspase inhibitors. RIP3 is phosphorylated at Ser227 and targets the phosphorylation of mixed lineage kinase domain-like protein, which is critical for necroptosis. In mice, RIP3 is phosphorylated at Thr231 and Ser232, leading to association with MLKL and necroptosis.
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