RIP kinase

Cytokine stimulation, pathogen infection, DNA damage or inflammation can initiate cellular signaling pathways that lead to diverse responses, including immune cell activation and death. The receptor-interacting protein (RIP) kinase family members have emerged as essential sensors of intracellular and extracellular stresses. They have been demonstrated to play an important role in not only inflammation and other immune responses, but also in death-inducing processes. The RIP kinases now contain seven members, all of which share a homologous kinase domain but have different functional domains.
 RIP1 contains a C-terminal death domain, through which RIP1 can be recruited to signaling complexes that initiate different pathways. RIP2 bears a caspase activation and recruitment domain (CARD). RIP3 has a C-terminus that is unique among all known protein domains. However, a RIP homotypic interaction motif (RHIM) found in the intermediate domain of RIP1 was also identified in the C-terminus of RIP3. The RHIM domain is likely to mediate protein–protein interactions, since it is required for the interaction between RIP3 and RIP1. RIP4 and RIP5 are characterized by the ankyrin repeats in their C-terminus. RIP6 and RIP7 have a leucine-rich repeat motif that may have a role in the recognition of damage-, pathogen- or stress-associated molecular patterns. Additionally, they both harbor Ros of complex proteins/C-terminal of Roc domains. Upon binding of GTP to the Roc domain, the RIP6 protein kinase activity is stimulated. Evidence was provided that the C-terminal of Roc domain might play a role in transmitting stimulating signals to the kinase domain. It is reasonable to deduce that the C-terminal domains of RIP family members play key roles in determining the diverse functions of different RIP kinases. 
RIP1 is a key mediator of several signaling pathways that lead to the activation of MAPKs and NF-κB, as well as cell death. RIP2 is critical for signaling from NOD-like receptors and can trigger MAPKs and NF-κB activation. The role of RIP3 is major in the induction of necrosis: it may participate in the process of apoptosis and regulate NF-κB signaling. RIP4 mainly functions in the activation of JNK and NF-κB pathways. These RIP kinases are involved in many cellular signaling pathways, regulating inflammatory responses and cell death or survival. Current knowledge of RIP kinases has suggested therapeutic potential in targeting RIP family kinases in the treatment of diseases of inflammation, ischemia and neurodegeneration.


1.Zhang D,et al. Cell Mol Immunol. 2010;7(4):243–249.