RIPK1 (Homo sapiens)
Description [+]
- Synonyms: RIPK1, RIP
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Receptor-interacting serine/threonine-protein kinase 1 (EC 2.7.11.1)(Serine/threonine-protein kinase RIP)(Cell death protein RIP)(Receptor-interacting protein) [Source:UniProtKB/Swiss-Prot;Acc:Q13546]
- Family: Death Domain-containing protein : other
- Process: necroptosis, apoptosis,
- Pathways: TNF/NF-kappaB signaling,
- Criteria: manually curated
- Curator comment:
- Mouse ortholog(s): Ripk1
- WIKI: RIPK1-H_sapiens
References [+]
- Identification of RIP1 kinase as a specific cellular target of necrostatins.
- Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J
- Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis. Nat Chem Biol. 2008 May;4(5):313-21.
- TNF-alpha induces two distinct caspase-8 activation pathways.
- Wang L, Du F, Wang X
- The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP. Cell. 2008 May 16;133(4):693-703.
- References from Mouse ortholog(s):
- RIP kinases at the crossroads of cell death and survival.
- Declercq W, Vanden Berghe T, Vandenabeele P
- Protein kinases of the receptor interacting protein (RIP) family collaborate with death receptor proteins to regulate cell death. Recent studies (Cho et al., 2009; He et al., 2009; Zhang et al., 2009) reveal that the RIP3 kinase functions with RIP1 at the crossroads of apoptosis, necroptosis, and cell survival. Cell. 2009 Jul 23;138(2):229-32.
- RIP kinases at the crossroads of cell death and survival.
- Declercq W, Vanden Berghe T, Vandenabeele P
- Protein kinases of the receptor interacting protein (RIP) family collaborate with death receptor proteins to regulate cell death. Recent studies (Cho et al., 2009; He et al., 2009; Zhang et al., 2009) reveal that the RIP3 kinase functions with RIP1 at the crossroads of apoptosis, necroptosis, and cell survival. Cell. 2009 Jul 23;138(2):229-32.
- The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation.
- Hur GM, Lewis J, Yang Q, Lin Y, Nakano H, Nedospasov S, Liu ZG
- The transcription factor NF-kappaB is activated when cells are exposed to genotoxic stress. It has been suggested that DNA damage will trigger a cytoplasmic signaling that leads to the activation of IKK and NF-kappaB, but the signaling components upstream of IKK have not yet been identified. Here we report that the receptor interacting protein, RIP, is the IKK upstream component, essential for the activation of NF-kappaB by DNA damage. Also, our findings suggest that this NF-kappaB activation by DNA damage is not mediated by autocrine or TNF-R1 signaling pathway. In wild-type fibroblasts, DNA damage induced by agents such as adriamycin, campthothecin, and ionizing radiation induces NF-kappaB activation. We found, however, that DNA damage failed to activate NF-kappaB in RIP-/- fibroblasts. The induction of IkappaBalpha degradation by DNA damage was normal in TNF-R1-/-, TRAF2-/-, TRAF5-/- and FADD-/- fibroblasts or when de novo protein synthesis was blocked. More importantly, the reconstitution of RIP expression in RIP-/- cells restores DNA damage-induced NF-kappaB activation. We also found that RIP forms a complex with IKK in response to DNA damage. Therefore, our study provides a possible mechanism for the initiation of the cytoplasmic signaling to activate NF-kappaB in response to DNA damage. Genes Dev. 2003 Apr 1;17(7):873-82. Epub 2003 Mar 21.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
Source | Domain Name | Start | End |
---|---|---|---|
PFAM A | Pkinase | 17 | 285 |
PFAM A | Pkinase_Tyr | 17 | 285 |
PFAM A | Death | 584 | 669 |
Protein sequence [+]
RIPK1 | Homo sapiens | 9606 | length:671
MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEAL
LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL
EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD
GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC
IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED
VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA
PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF
AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD
PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ
IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN
CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID
LLSSLIYVSQN
LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL
EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD
GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC
IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED
VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA
PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF
AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD
PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ
IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN
CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID
LLSSLIYVSQN
Structure links:
- Smartdomain prediction information: SM00219
- Smartdomain prediction information: SM00220
- Smartdomain prediction information: SM00005
- Prosite motif and domain information: PS00108
- Profile motif and domain profile information: PS50017
- Profile motif and domain profile information: PS50011
- Interpro domain information: Q13546
- PFAM domain and domain family information: Q13546
Evolution [+]
View protein alignment and tree with Jalview:  
Explore tree at phylomeDB:   Click here.
Homologs list [+]
Name | Relationship | Species |
---|---|---|
NP_989733.1 | orthology | Chicken |
RIPK1 | orthology | Chimpanzee |
NP_001030184.1 | orthology | Cow |
RIPK1 | orthology | Dog |
RIPK1 | orthology | Fugu |
RIPK1 | orthology | Gasterosteus |
RIPK1 | orthology | Gorilla |
RIPK1 | orthology | Horse |
RIPK1 | orthology | Lyzard |
RIPK1 | orthology | Macaca |
RIPK1 | orthology | Medaka |
RIPK1 | orthology | Monodelphis |
Ripk1 | orthology | Mouse |
RIPK1 | orthology | Orangutan |
RIPK1 | orthology | Ornithorhynchus |
RIPK1 | orthology | Rabbit |
NP_001100820.1 | orthology | Rat |
RIPK1 | orthology | Tetraodon |
RIPK1 | orthology | Xenopus |
RIPK1 | orthology | Zebra finch |
NP_001036815.1 | orthology | Zebrafish |
MATK | paralogy | Chicken |
HCK | paralogy | Chicken |
NP_990363.1 | paralogy | Chicken |
ANKK1 | paralogy | Chicken |
NP_001026114.1 | paralogy | Chicken |
RIPK4 | paralogy | Chicken |
NP_001006390.1 | paralogy | Chicken |
RIPK3 | paralogy | Chimpanzee |
CSK | paralogy | Chimpanzee |
IGF1R | paralogy | Chimpanzee |
RIPK4 | paralogy | Chimpanzee |
RIPK2 | paralogy | Chimpanzee |
MATK | paralogy | Chimpanzee |
LYN | paralogy | Chimpanzee |
INSRR | paralogy | Cow |
NP_001032218.2 | paralogy | Cow |
RIPK2_BOVIN | paralogy | Cow |
NP_001095354.1 | paralogy | Cow |
IPI00686890.1 | paralogy | Cow |
NP_001093797.1 | paralogy | Cow |
CSK_BOVIN | paralogy | Cow |
NP_001029506.1 | paralogy | Cow |
LYN | paralogy | Dog |
RIPK2 | paralogy | Dog |
LCK | paralogy | Dog |
RIPK3 | paralogy | Dog |
ANKK1 | paralogy | Dog |
MATK | paralogy | Dog |
RIPK4 | paralogy | Fugu |
LYN | paralogy | Fugu |
RIPK2 | paralogy | Fugu |
IGF1R (1 of 2) | paralogy | Fugu |
T_rubripes_ENSTRUP00000020710 | paralogy | Fugu |
MATK | paralogy | Fugu |
CSK | paralogy | Fugu |
HCK | paralogy | Gasterosteus |
CSK (2 of 2) | paralogy | Gasterosteus |
MATK | paralogy | Gasterosteus |
IGF1R (2 of 2) | paralogy | Gasterosteus |
LYN | paralogy | Gasterosteus |
RIPK4 | paralogy | Gasterosteus |
RIPK3 | paralogy | Gorilla |
CSK | paralogy | Gorilla |
RIPK4 | paralogy | Horse |
RIPK3 | paralogy | Horse |
LYN | paralogy | Horse |
CSK | paralogy | Horse |
HCK | paralogy | Horse |
MATK | paralogy | Horse |
RIPK2 | paralogy | Horse |
LCK | paralogy | Horse |
IGF1R | paralogy | Human |
LYN | paralogy | Human |
ANKK1 | paralogy | Human |
MATK | paralogy | Human |
RIPK4 | paralogy | Human |
RIPK3 | paralogy | Human |
RIPK3 | paralogy | Human |
CSK | paralogy | Human |
H_sapiens_ENSP00000220751 | paralogy | Human |
RIPK4 | paralogy | Lyzard |
HCK | paralogy | Lyzard |
RIPK2 | paralogy | Lyzard |
IGF1R | paralogy | Macaca |
LYN | paralogy | Macaca |
RIPK4 | paralogy | Macaca |
RIPK3 | paralogy | Macaca |
RIPK2 | paralogy | Macaca |
CSK | paralogy | Macaca |
CSK (2 of 2) | paralogy | Medaka |
RIPK2 | paralogy | Medaka |
IGF1R (1 of 2) | paralogy | Medaka |
RIPK4 | paralogy | Medaka |
LYN | paralogy | Medaka |
BLK | paralogy | Medaka |
MATK | paralogy | Monodelphis |
RIPK2 | paralogy | Monodelphis |
LYN | paralogy | Monodelphis |
BLK | paralogy | Monodelphis |
IGF1R | paralogy | Monodelphis |
ANKK1 | paralogy | Monodelphis |
RIPK4 | paralogy | Monodelphis |
INSR | paralogy | Monodelphis |
Ripk4 | paralogy | Mouse |
Ripk3 | paralogy | Mouse |
Ankk1 | paralogy | Mouse |
Csk | paralogy | Mouse |
M_musculus_ENSMUSP00000038833 | paralogy | Mouse |
Lyn | paralogy | Mouse |
Matk | paralogy | Mouse |
LCK | paralogy | Orangutan |
RIPK3 | paralogy | Orangutan |
CSK | paralogy | Orangutan |
Q5RCL1_PONPY | paralogy | Orangutan |
RIPK4 | paralogy | Orangutan |
LYN | paralogy | Orangutan |
RIPK2 | paralogy | Orangutan |
IGF1R | paralogy | Ornithorhynchus |
LYN | paralogy | Ornithorhynchus |
RIPK4 | paralogy | Ornithorhynchus |
LOC690279 | paralogy | Rat |
NP_001100573.1 | paralogy | Rat |
Lyn | paralogy | Rat |
Ripk2 | paralogy | Rat |
Csk | paralogy | Rat |
Matk | paralogy | Rat |
Ripk3 | paralogy | Rat |
RIPK2 | paralogy | Tetraodon |
RIPK4 | paralogy | Tetraodon |
CSK (2 of 2) | paralogy | Tetraodon |
LYN | paralogy | Tetraodon |
IGF1R (2 of 2) | paralogy | Tetraodon |
csk-1 | paralogy | Worm |
ripk4 | paralogy | Xenopus |
RIPK2 | paralogy | Xenopus |
ANKK1 | paralogy | Xenopus |
CSK | paralogy | Xenopus |
ANKK1 | paralogy | Zebra finch |
HCK | paralogy | Zebra finch |
T_guttata_ENSTGUP00000008956 | paralogy | Zebra finch |
LYN | paralogy | Zebra finch |
RIPK2 | paralogy | Zebra finch |
csk | paralogy | Zebrafish |
si:dkey-33i22.2 | paralogy | Zebrafish |
igf1ra | paralogy | Zebrafish |
zgc:92124 | paralogy | Zebrafish |
igf1rb | paralogy | Zebrafish |
zgc:55705 | paralogy | Zebrafish |
LOC569951 | paralogy | Zebrafish |
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Gene Ontology [+]
GO id | Name | Ontology type | Evidence |
---|---|---|---|
GO:0007165 | signal transduction | biological_proccess | IEA |
GO:0034612 | response to tumor necrosis factor | biological_proccess | IMP |
GO:0006917 | induction of apoptosis | biological_proccess | IMP |
GO:0051092 | positive regulation of NF-kappaB transcription factor activity | biological_proccess | IMP |
GO:0033209 | tumor necrosis factor-mediated signaling pathway | biological_proccess | IC |
GO:0045768 | positive regulation of anti-apoptosis | biological_proccess | TAS |
GO:0080010 | regulation of oxygen and reactive oxygen species metabolic process | biological_proccess | TAS |
GO:0007257 | activation of JUN kinase activity | biological_proccess | TAS |
GO:0010940 | positive regulation of necrotic cell death | biological_proccess | IMP |
GO:0060555 | biological_proccess | IMP | |
GO:0046777 | protein amino acid autophosphorylation | biological_proccess | IDA |
GO:0007165 | signal transduction | biological_proccess | TAS |
GO:0008633 | activation of pro-apoptotic gene products | biological_proccess | EXP |
GO:0043123 | positive regulation of I-kappaB kinase/NF-kappaB cascade | biological_proccess | IEP |
GO:0006468 | protein amino acid phosphorylation | biological_proccess | IEA |
GO:0005515 | protein binding | mollecular_function | IEA |
GO:0070513 | death domain binding | mollecular_function | IPI |
GO:0005123 | death receptor binding | mollecular_function | IPI |
GO:0004674 | protein serine/threonine kinase activity | mollecular_function | IEA |
GO:0004713 | protein tyrosine kinase activity | mollecular_function | IEA |
GO:0005524 | ATP binding | mollecular_function | IEA |
GO:0000166 | nucleotide binding | mollecular_function | IEA |
GO:0005515 | protein binding | mollecular_function | IPI |
GO:0016740 | transferase activity | mollecular_function | IEA |
GO:0004672 | protein kinase activity | mollecular_function | IEA |
GO:0043235 | receptor complex | cell_component | IDA |
GO:0031264 | death-inducing signaling complex | cell_component | IDA |
GO:0005739 | mitochondrion | cell_component | IDA |
GO:0005829 | cytosol | cell_component | EXP |
GO:0005737 | cytoplasm | cell_component | IEA |
Check GO Evidence Codes here
KEGG Pathways [+]
Curated Isoforms [+]
Transcript | Translation |
---|---|
OTTHUMT00000039659 * | OTTHUMP00000015955 * |
OTTHUMT00000039660 | |
OTTHUMT00000039661 |
Info from The Vertebrate Genome Annotation (VEGA) database.
(*) Canonical transcript and translation forms.
Information from other databases [+]
- Gene info from HGNC [?] :10019
- Gene related info from GeneCards [?] : RIPK1
- Ensembl genome browser [?] : ENSG00000137275
- Expression info from Arrayexpress [?] : ENSG00000137275
- Protein expression from Protein Atlas: [?] ENSG00000137275
- Community gene edition from Wikigenes: [?] 8737
- OMIM gene information: 603453
- OMIM disease information:
Click on [?] for more information.