Ripk1
entrez
19766
canonical
uniprot
Q60855
canonical
ensembl
ENSMUSG00000021408
resolver
ensp
ENSMUSP00000021844
resolver
ensp
ENSMUSP00000129831
resolver
enst
ENSMUST00000021844
resolver
enst
ENSMUST00000167374
resolver
genesymbol
Ripk1
resolver
genesymbol_syn
Rinp
resolver
genesymbol_syn
Rip
resolver
uniprot
Q3U0J3
resolver
uniprot
Q8CD90
resolver
uniprot_entry
RIPK1_MOUSE
resolver
uniprot_sec
Q3U0J3
resolver
uniprot_sec
Q8CD90
resolver
activity_regulation
ACTIVITY REGULATION: Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex. {ECO:0000269|PubMed:28701375}.
uniprot
proteins
amino_acid_sequence
MQPDMSLDNIKMASSDLLEKTDLDSGGFGKVSLCYHRSHGFVILKKVYTGPNRAEYNEVLLEEGKMMHRLRHSRVVKLLGIIIEEGNYSLVMEYMEKGNLMHVLKTQIDVPLSLKGRIIVEAIEGMCYLHDKGVIHKDLKPENILVDRDFHIKIADLGVASFKTWSKLTKEKDNKQKEVSSTTKKNNGGTLYYMAPEHLNDINAKPTEKSDVYSFGIVLWAIFAKKEPYENVICTEQFVICIKSGNRPNVEEILEYCPREIISLMERCWQAIPEDRPTFLGIEEEFRPFYLSHFEEYVEEDVASLKKEYPDQSPVLQRMFSLQHDCVPLPPSRSNSEQPGSLHSSQGLQMGPVEESWFSSSPEYPQDENDRSVQAKLQEEASYHAFGIFAEKQTKPQPRQNEAYNREEERKRRVSHDPFAQQRARENIKSAGARGHSDPSTTSRGIAVQQLSWPATQTVWNNGLYNQHGFGTTGTGVWYPPNLSQMYSTYKTPVPETNIPGSTPTMPYFSGPVADDLIKYTIFNSSGIQIGNHNYMDVGLNSQPPNNTCKEESTSRHQAIFDNTTSLTDEHLNPIRENLGRQWKNCARKLGFTESQIDEIDHDYERDGLKEKVYQMLQKWLMREGTKGATVGKLAQALHQCCRIDLLNHLIRASQS
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
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). {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:12654725, ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30185824, ECO:0000269|PubMed:30867408, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31358656, ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:33397971}.
uniprot
proteins
mass_dalton
74854
uniprot
proteins
mutagenesis
MUTAGEN 6; /note="S->A: Loss of phosphorylation. Does not protect cells from TNF-induced cell death."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 6; /note="S->D: Phosphomimetic mutant. Does not protect cells from TNF-induced cell death."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 25; /note="S->A: Loss of phosphorylation. Does not protect cells from TNF-induced cell death."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 25; /note="S->D: Phosphomimetic mutant. Significant loss of kinase activity. Protects cells from TNF-induced cell death."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 45; /note="K->A: Loss of kinase activity. Protects cells from TNF-induced cell death."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 45; /note="K->M: Loss of kinase activity."; /evidence="ECO:0000269|PubMed:29440439"; MUTAGEN 138; /note="D->N: Abolished protein kinase activity and ability to regulate apoptosis and necroptosis. Knockin mice are viable."; /evidence="ECO:0000269|PubMed:24557836"; MUTAGEN 138; /note="D->N: Loss of kinase activity."; /evidence="ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281"; MUTAGEN 321; /note="S->A: Loss of phosphorylation. Promotes activation of its kinase activity, proteolytic cleavage, ubiquitination and interaction with FADD to mediate apoptosis. Loss of phosphorylation at Ser-332 and Ser-334; when associated with A-332; A-334 and A-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 321; /note="S->E: Inhibits its proteolytic cleavage and interaction with FADD. Promotes its interaction with RIPK3 to mediate necroptosis; when associated with E-332; E-334 and E-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 325; /note="D->A: Loss of CASP8-mediated cleavage. Promotes both FADD-dependent apoptosis and RIPK3-dependent necroptosis, thus leading to embryonic lethality at midgestation stages in knockin mice. Heterozygous knockin mice are viable and grossly normal, but are hyperresponsive to inflammatory stimuli."; /evidence="ECO:0000269|PubMed:30867408, ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827281"; MUTAGEN 325; /note="D->V,H: Loss of CASP8-mediated cleavage. Embryonic lethality in knockin mice. Promotes activation of the protein kinase activity, leading to increased cell death."; /evidence="ECO:0000269|PubMed:31827280"; MUTAGEN 332; /note="S->A: Loss of phosphorylation at Ser-332 and Ser-334; when associated with A-321; A-334 and A-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 332; /note="S->E: Promotes its interaction with RIPK3 to mediate necroptosis; when associated with E-321; E-334 and E-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 334; /note="S->A: Loss of phosphorylation at Ser-332 and Ser-334; when associated with A-321; A-332 and A-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 334; /note="S->E: Promotes its interaction with RIPK3 to mediate necroptosis; when associated with E-321; E-332 and E-336."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 336; /note="S->A: Loss of phosphorylation at Ser-332 and Ser-334; when associated with A-321; A-332 and A-334."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 336; /note="S->E: Promotes its interaction with RIPK3 to mediate necroptosis; when associated with E-321; E-332 and E-334."; /evidence="ECO:0000269|PubMed:28842570"; MUTAGEN 376; /note="K->R: Loss of ubiquitination. Decreases TNF-mediated NF-kappaB activation. Increases interaction with CFLAR, CASP8, FADD and RIPK3. Decreases interaction with MAP3K7. Enhances kinase activity and promotes apoptosis and necroptosis. Knockin mice display early embryonic lethality resulting from excessive cell death and severe inflammation."; /evidence="ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887"; MUTAGEN 529..531; /note="QIG->AAA: In RIPK1(mRHIM); perinatal lethality in knockin mice caused by Ripk3- and Zbp1-dependent necroptosis. Lethality is prevented by Ripk3, Mlkl or Zbp1 deficiency. Knockin mice do not show defects caused by Casp8-dependent apoptosis observed in knockout mice."; /evidence="ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682"; MUTAGEN 584; /note="K->R: Blocks homodimerization, activation of its kinase activity, formation of complex IIa, necroptosis and apoptosis."; /evidence="ECO:0000269|PubMed:29440439
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:30867408, ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}.; PTM: 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). {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:30988283}.; PTM: Deubiquitinated by USP7; this modification is required for TNF-induced apoptosis. {ECO:0000250|UniProtKB:Q13546}.; PTM: 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-induced NF-kappa-B signaling (By similarity). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-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). {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
12654725
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
17301840
uniprot
proteins
pubmed
18239685
uniprot
proteins
pubmed
18442983
uniprot
proteins
pubmed
19590578
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
23283962
uniprot
proteins
pubmed
24557836
uniprot
proteins
pubmed
24813849
uniprot
proteins
pubmed
24813850
uniprot
proteins
pubmed
25459879
uniprot
proteins
pubmed
27819681
uniprot
proteins
pubmed
27819682
uniprot
proteins
pubmed
28701375
uniprot
proteins
pubmed
28842570
uniprot
proteins
pubmed
29440439
uniprot
proteins
pubmed
29883609
uniprot
proteins
pubmed
30185824
uniprot
proteins
pubmed
30498077
uniprot
proteins
pubmed
30867408
uniprot
proteins
pubmed
30988283
uniprot
proteins
pubmed
31358656
uniprot
proteins
pubmed
31457011
uniprot
proteins
pubmed
31511692
uniprot
proteins
pubmed
31519886
uniprot
proteins
pubmed
31519887
uniprot
proteins
pubmed
31827280
uniprot
proteins
pubmed
31827281
uniprot
proteins
pubmed
33397971
uniprot
proteins
pubmed
34471287
uniprot
proteins
pubmed
7538908
uniprot
proteins
sequence_length
656
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23283962, ECO:0000269|PubMed:7538908}. Cell membrane {ECO:0000250|UniProtKB:Q9ZUF4}.
uniprot
proteins