Receptor Interacting Protein Kinases

Receptor Interacting Protein (RIP) kinases are characterized by a homologous kinase domain, but have distinct non-kinase regions, which are key to the specific function of each RIP kinase. They have key roles in various biological processes, including innate immunity, inflammation and regulation of cell death.

RIP1-5 all have a N-terminal kinase domain. In addition to the kinase domain RIP1 contains an intermediate domain and a C-terminal death domain (DD), which binds to death receptors, such as TNF-R1, and adaptor proteins, such as TNF-receptor-associated death domain (TRADD). RIP1 is also able to bind to other kinases including RIP3. RIP2 also contains an intermediate domain, but has a C-terminal caspase activation and recruitment domain (CARD). RIP3 contains the N-terminal but lacks the intermediate domain and has a C-terminal sequence containing a RHIM (RIP homotypic interaction motif), also found in the intermediate domain of RIP1. Both RIP4 and 5 have C-terminal ankyrin domains.

RIP1 is widely expressed and along with RIP3 is an important mediator of regulated cell death. Following activation of death receptors, including TNF-R1, Fas and TNF-related apoptosis inducing ligand (TRAIL), a complex (complex I) comprising the TNFR-associated death protein (TRADD), TRAF2, cellular inhibitor of apoptosis (cIAP) and RIP1 is formed. This activates NF-κB, which promotes the expression of antiapoptotic proteins. Deubiquination of RIP1 enables its release from complex I and formation of a complex with Fas-associated death domain (FADD) and procaspase 8, known as complex II. Complex II promotes activation of procaspase 8 which triggers a caspase cascade culminating in apoptosis. However, if the caspases remain inactive, RIP1 forms a complex with RIP3, known as the necrosome, and necroptosis ensues. Thus, RIP1 is important in controlling the switch between inflammation and apoptosis.

RIP2 is an important mediator of the innate immune response. When bacterial peptides activate the cytosolic receptors NOD1 and NOD2, the CARD domain of RIP2 interacts with the CARD domain of NOD1/2, activating NF-κB and triggering the expression of inflammatory and antibacterial proteins, as well as autophagy. The functions of RIP4, 5 and 6 are less well understood; RIP4 has been shown to activate NF-κB and has a role in keratinocyte differentiation and cutaneous inflammation, while overexpression of RIP5 has been shown to drive cell apoptosis, but its physiological role is yet to be determined. RIP6 (LRRK1) is associated with the pathogenesis of Parkinson's disease.

Receptor Interacting Protein Kinase Gene Data