Recombinant Mouse Receptor-interacting serine/threonine-protein kinase 1 (Ripk1)

Function

Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:24557836, PubMed:24813849, PubMed:24813850, PubMed:27819681, PubMed:28842570, PubMed:31511692, PubMed:31827280, PubMed:31827281, PubMed:33397971). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:24557836, PubMed:24813849, PubMed:24813850, PubMed:28842570, PubMed:31519886, PubMed:31519887). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (PubMed:31519886, PubMed:31519887). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (PubMed:27819681, PubMed:27819682, PubMed:28842570, PubMed:29440439, PubMed:30988283, PubMed:31519886, PubMed:31519887). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (PubMed:24557836, PubMed:24813849, PubMed:24813850). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:24557836, PubMed:27819681, PubMed:27819682, PubMed:31358656). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:31358656). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (PubMed:30185824, PubMed:30867408). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). Phosphorylates DAB2IP at 'Ser-728' in a TNF-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (By similarity). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (PubMed:12654725, PubMed:19590578)

Subcellular Location

Cytoplasm; Cell membrane

Tissue Specificity

Found at low levels in all tissues

Subunit

(Microbial infection) Interacts with Murid herpesvirus 1 protein RIR1

• Stanger B.Z. et al. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. — Cell (1995)
• Carninci P. et al. The transcriptional landscape of the mammalian genome. — Science (2005)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Hur G.M. et al. The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. — Genes Dev. (2003)
• Festjens N. et al. RIP1, a kinase on the crossroads of a cell's decision to live or die. — Cell Death Differ. (2007)
• Upton J.W. et al. Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1. — J. Biol. Chem. (2008)
• Iha H. et al. Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation. — EMBO J. (2008)
• Rebsamen M. et al. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. — EMBO Rep. (2009)