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Ripk1

Domain

The death domain mediates dimerization and activation of its kinase activity during necroptosis and apoptosis (PubMed:29440439). It engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling (By similarity).

The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).

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-alpha-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).

Post-translational modifications

Proteolytically cleaved by CASP8 at Asp-325 (PubMed:30867408, PubMed:31511692, PubMed:31827280). Cleavage is crucial for limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:30867408, PubMed:31511692, PubMed:31827280, PubMed:31827281). Cleavage abolishes NF-kappa-B activation and enhances the interaction of TRADD with FADD (By similarity). Proteolytically cleaved by CASP6 during intrinsic apoptosis (By similarity).

RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (By similarity). Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283). Phosphorylated at Ser-321 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (PubMed:28842570). This phosphorylation positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570).

Deubiquitinated by USP7; this modification is required for TNF-alpha-induced apoptosis.

Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (By similarity). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (By similarity). Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NF-kappa-B signaling (By similarity). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NF-kappa-B signaling (By similarity). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:28701375). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (PubMed:28701375). Polyubiquitinated with 'Lys-48' by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (By similarity). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (By similarity). Ubiquitination at Lys-376 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-321 mediated by MAP3K7 (PubMed:28842570, PubMed:31519886, PubMed:31519887). This ubiquitination is required for NF-kB activation, suppresses RIPK1 kinase activity and plays a critical role in preventing cell death during embryonic development (PubMed:31519886, PubMed:31519887).

Sequence Similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Tissue Specificity

Found at low levels in all tissues.

Cellular localization

Alternative names

Rinp, Rip, Ripk1, Receptor-interacting serine/threonine-protein kinase 1, Cell death protein RIP, Receptor-interacting protein 1, RIP-1

swissprot:Q60855 entrezGene:19766

Other research areas