RIPK1
entrez
8737
canonical
uniprot
Q13546
canonical
ensembl
ENSG00000137275
resolver
ensp
ENSP00000259808
resolver
ensp
ENSP00000369773
resolver
ensp
ENSP00000528549
resolver
ensp
ENSP00000637637
resolver
genesymbol
RIPK1
resolver
genesymbol_syn
RIP
resolver
genesymbol_syn
RIP1
resolver
hgnc
HGNC:10019
resolver
uniprot
A0AV89
resolver
uniprot
B2RAG1
resolver
uniprot
B4E3F9
resolver
uniprot
Q13180
resolver
uniprot
Q59H33
resolver
uniprot_entry
RIPK1_HUMAN
resolver
uniprot_sec
A0AV89
resolver
uniprot_sec
B2RAG1
resolver
uniprot_sec
B4E3F9
resolver
uniprot_sec
Q13180
resolver
uniprot_sec
Q59H33
resolver
activity_regulation
ACTIVITY REGULATION: Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By similarity). Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4 (PubMed:23473668). {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:23473668}.
uniprot
proteins
amino_acid_sequence
MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEALLEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIILEIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEEDVKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFAPSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPFAQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLDPGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQIGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKNCARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRIDLLSSLIYVSQN
uniprot
proteins
disease_involvement
DISEASE: Immunodeficiency 57 with autoinflammation (IMD57) [MIM:618108]: An autosomal recessive primary immunodeficiency characterized by lymphopenia and recurrent viral, bacterial, and fungal infections. Patients exhibit early-onset inflammatory bowel disease involving the upper and lower gastrointestinal tract, and develop progressive polyarthritis. {ECO:0000269|PubMed:30026316}. Note=The disease is caused by variants affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis. {ECO:0000269|PubMed:30026316}.; DISEASE: Autoinflammation with episodic fever and lymphadenopathy (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder characterized by early onset of recurrent episodes of unexplained fever, lymphadenopathy, hepatosplenomegaly, and increased levels of inflammatory cytokines and chemokines in patient serum. {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. Note=The disease is caused by variants affecting the gene represented in this entry.
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:17703191, PubMed:24144979, PubMed:31827280, PubMed:31827281, PubMed:32657447, PubMed:35831301). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). 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 (By similarity). 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 (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). 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:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). 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 (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:15310755, PubMed:17389591). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity). {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:11101870, ECO:0000269|PubMed:15310755, ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:17703191, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:24144979, ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:32657447, ECO:0000269|PubMed:35831301}.
uniprot
proteins
mass_dalton
75931
uniprot
proteins
mutagenesis
MUTAGEN 25; /note="S->D: Phosphomimetic mutant. Significant loss of kinase activity."; /evidence="ECO:0000269|PubMed:30988283"; MUTAGEN 45; /note="K->A: Abolishes kinase activity."; /evidence="ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:8612133"; MUTAGEN 161; /note="S->A: Decreases RIPK1 kinase activity."; /evidence="ECO:0000269|PubMed:18408713"; MUTAGEN 161; /note="S->E: No effect on RIPK1 autophosphorylation."; /evidence="ECO:0000269|PubMed:18408713"; MUTAGEN 324; /note="D->K: Abolishes cleavage by caspase-8."; /evidence="ECO:0000269|PubMed:10521396"; MUTAGEN 377; /note="K->R: Abolishes RIP-mediated NF-Kappa-B activation."; /evidence="ECO:0000269|PubMed:16603398"; MUTAGEN 536; /note="S->C: Strongly reduced homodimerization and interaction with RIPK3."; /evidence="ECO:0000269|PubMed:29681455"; MUTAGEN 539..542; /note="IQIG->AAAA: Abolished cleavage by S.flexneri OspD3."; /evidence="ECO:0000269|PubMed:32657447"; MUTAGEN 599; /note="K->R: Blocks homodimerization, necroptosis and apoptosis."; /evidence="ECO:0000269|PubMed:29440439"; MUTAGEN 603; /note="R->A: Abolished GlcNAcylation by E.coli NleB1."; /evidence="ECO:0000269|PubMed:30979585
uniprot
proteins
post_translational_modification
PTM: (Microbial infection) Proteolytically cleaved by S.flexneri OspD3 within the RIP homotypic interaction motif (RHIM), leading to its degradation and inhibition of necroptosis. {ECO:0000269|PubMed:32657447}.; PTM: Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396, PubMed:31827280, PubMed:31827281). Cleavage is crucial for limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Cleavage abolishes NF-kappa-B activation and enhances the interaction of TRADD with FADD (PubMed:10521396). Proteolytically cleaved by CASP6 during intrinsic apoptosis (PubMed:22858542). {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:10521396, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}.; PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283). Phosphorylated at Ser-320 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:18408713, ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280}.; PTM: Deubiquitinated by USP7; this modification is required for TNF-induced apoptosis. {ECO:0000269|PubMed:24144979}.; PTM: Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (PubMed:15258597, PubMed:16603398, PubMed:17703191, PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, Ref.36). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (PubMed:15258597). 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 (PubMed:15258597). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-induced NF-kappa-B signaling (PubMed:18450452, Ref.36). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (By similarity). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (PubMed:29883609). Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity). This ubiquitination is required for NF-kB activation, suppresses RIPK1 kinase activity and plays a critical role in preventing cell death during embryonic development (By similarity). {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:16603398, ECO:0000269|PubMed:18450452, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:29883609, ECO:0000269|Ref.36}.; PTM: (Microbial infection) Glycosylated at Arg-603 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions. {ECO:0000305|PubMed:23955153}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
TKL Ser/Thr protein kinase family
uniprot
proteins
pubmed
10356400
uniprot
proteins
pubmed
10358032
uniprot
proteins
pubmed
10409763
uniprot
proteins
pubmed
10521396
uniprot
proteins
pubmed
11101870
uniprot
proteins
pubmed
11116146
uniprot
proteins
pubmed
11734559
uniprot
proteins
pubmed
11854271
uniprot
proteins
pubmed
14574404
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14754897
uniprot
proteins
pubmed
15144186
uniprot
proteins
pubmed
15258597
uniprot
proteins
pubmed
15310755
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16127453
uniprot
proteins
pubmed
16603398
uniprot
proteins
pubmed
17301840
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17389591
uniprot
proteins
pubmed
17449468
uniprot
proteins
pubmed
17703191
uniprot
proteins
pubmed
18408713
uniprot
proteins
pubmed
18442983
uniprot
proteins
pubmed
18450452
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
19524512
uniprot
proteins
pubmed
19524513
uniprot
proteins
pubmed
20354226
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21455173
uniprot
proteins
pubmed
21887730
uniprot
proteins
pubmed
21931591
uniprot
proteins
pubmed
22265414
uniprot
proteins
pubmed
22858542
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23473668
uniprot
proteins
pubmed
23955153
uniprot
proteins
pubmed
24130170
uniprot
proteins
pubmed
24144979
uniprot
proteins
pubmed
24204270
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
25459879
uniprot
proteins
pubmed
25674983
uniprot
proteins
pubmed
25736436
uniprot
proteins
pubmed
28659487
uniprot
proteins
pubmed
29440439
uniprot
proteins
pubmed
29681455
uniprot
proteins
pubmed
29883609
uniprot
proteins
pubmed
30026316
uniprot
proteins
pubmed
30979585
uniprot
proteins
pubmed
30988283
uniprot
proteins
pubmed
31457011
uniprot
proteins
pubmed
31827280
uniprot
proteins
pubmed
31827281
uniprot
proteins
pubmed
32657447
uniprot
proteins
pubmed
35831301
uniprot
proteins
pubmed
7538908
uniprot
proteins
pubmed
8612133
uniprot
proteins
pubmed
9044836
uniprot
proteins
pubmed
9927690
uniprot
proteins
sequence_length
671
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q60855}. Cell membrane {ECO:0000250|UniProtKB:Q9ZUF4}.
uniprot
proteins