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Q13546 (RIPK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 153. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Receptor-interacting serine/threonine-protein kinase 1

EC=2.7.11.1
Alternative name(s):
Cell death protein RIP
Receptor-interacting protein 1
Short name=RIP-1
Serine/threonine-protein kinase RIP
Gene names
Name:RIPK1
Synonyms:RIP, RIP1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length671 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex. Ref.14 Ref.24 Ref.30 Ref.31

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.38

Enzyme regulation

Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4. Ref.38

Subunit structure

Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interact with MAVS/IPS1. Interacts with ZFAND5. Interacts with RBCK1 By similarity. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK3 and MLKL. Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner. Interacts with ARHGEF2. Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination. Ref.1 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.24 Ref.25 Ref.26 Ref.28 Ref.31 Ref.35 Ref.36 Ref.37

Subcellular location

Cytoplasm. Cell membrane By similarity.

Domain

Contains a C-terminal death domain (DD) that engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling. Ref.10

Post-translational modification

Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apoptotic signaling through the TRADD-FADD interaction. Ref.9

RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex.

Ubiquitinated by 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin. Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex. 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 NFkappa-B signaling. 'Lys-48'-linked polyubiquitination by RFFL also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NFkappa-B signaling. Linear polyubiquitinated; the head-to-tail polyubiquitination is mediated by the LUBAC complex. LPS-mediated activation of NF-kappa-B. Also ubiquitinated with 'Lys-11'-linked chains. Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B. Ref.20 Ref.22 Ref.26 Ref.34 Ref.35

Sequence similarities

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

Contains 1 death domain.

Contains 1 protein kinase domain.

Sequence caution

The sequence BAG65471.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processNecrosis
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processMyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

T cell apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

activation of JUN kinase activity

Traceable author statement PubMed 17979836. Source: BHF-UCL

activation of cysteine-type endopeptidase activity involved in apoptotic process

Traceable author statement. Source: Reactome

amyloid fibril formation

Inferred from mutant phenotype PubMed 22817896. Source: UniProtKB

apoptotic process

Inferred from mutant phenotype PubMed 21737330PubMed 22891283. Source: UniProtKB

apoptotic signaling pathway

Traceable author statement. Source: Reactome

cellular protein catabolic process

Inferred from direct assay Ref.24. Source: UniProtKB

cellular response to tumor necrosis factor

Inferred from direct assay Ref.24. Source: UniProtKB

extrinsic apoptotic signaling pathway

Inferred from direct assay Ref.8. Source: BHF-UCL

innate immune response

Traceable author statement. Source: Reactome

necroptotic process

Inferred from mutant phenotype PubMed 21737330PubMed 22265413Ref.36. Source: UniProtKB

necroptotic signaling pathway

Inferred from mutant phenotype Ref.14PubMed 16507998. Source: BHF-UCL

negative regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype PubMed 17047155. Source: UniProtKB

negative regulation of extrinsic apoptotic signaling pathway

Inferred from mutant phenotype PubMed 21525013. Source: UniProtKB

negative regulation of intrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

peptidyl-serine autophosphorylation

Inferred from direct assay Ref.38. Source: UniProtKB

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from direct assay Ref.24. Source: UniProtKB

positive regulation of JNK cascade

Inferred from direct assay Ref.24. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Inferred from mutant phenotype Ref.35. Source: UniProtKB

positive regulation of apoptotic process

Inferred from direct assay Ref.24. Source: UniProtKB

positive regulation of extrinsic apoptotic signaling pathway

Inferred from mutant phenotype PubMed 21525013PubMed 22274400. Source: UniProtKB

positive regulation of interleukin-8 production

Inferred from direct assay Ref.21. Source: BHF-UCL

positive regulation of macrophage differentiation

Inferred from mutant phenotype PubMed 17047155. Source: UniProtKB

positive regulation of necroptotic process

Inferred from mutant phenotype PubMed 22028622PubMed 22274400PubMed 22817896. Source: UniProtKB

positive regulation of programmed cell death

Inferred from mutant phenotype PubMed 16611992. Source: UniProtKB

positive regulation of protein phosphorylation

Inferred from mutant phenotype Ref.24. Source: UniProtKB

positive regulation of reactive oxygen species metabolic process

Traceable author statement PubMed 17979836. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay Ref.24. Source: UniProtKB

positive regulation of tumor necrosis factor production

Inferred from direct assay Ref.21. Source: BHF-UCL

positive regulation of type I interferon production

Traceable author statement. Source: Reactome

protein autophosphorylation

Inferred from direct assay Ref.1. Source: BHF-UCL

protein heterooligomerization

Inferred from mutant phenotype PubMed 22817896. Source: UniProtKB

protein homooligomerization

Inferred from direct assay PubMed 22817896. Source: UniProtKB

regulation of ATP:ADP antiporter activity

Inferred from mutant phenotype PubMed 16507998. Source: BHF-UCL

regulation of extrinsic apoptotic signaling pathway in absence of ligand

Traceable author statement. Source: Reactome

response to tumor necrosis factor

Inferred from mutant phenotype Ref.9. Source: BHF-UCL

ripoptosome assembly

Inferred from mutant phenotype PubMed 21737330. Source: UniProtKB

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

tumor necrosis factor-mediated signaling pathway

Inferred by curator Ref.1. Source: BHF-UCL

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

death-inducing signaling complex

Inferred from direct assay Ref.14. Source: BHF-UCL

membrane raft

Inferred from electronic annotation. Source: Ensembl

mitochondrion

Inferred from direct assay PubMed 16507998. Source: BHF-UCL

receptor complex

Inferred from direct assay Ref.1. Source: BHF-UCL

ripoptosome

Inferred from direct assay PubMed 21737330. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

death domain binding

Inferred from physical interaction Ref.1PubMed 9044836. Source: BHF-UCL

death receptor binding

Inferred from physical interaction Ref.8. Source: BHF-UCL

identical protein binding

Inferred from physical interaction PubMed 22817896. Source: IntAct

protein complex binding

Inferred from direct assay Ref.36. Source: UniProtKB

protein kinase activity

Inferred from direct assay PubMed 22265413. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.38. Source: UniProtKB

ubiquitin protein ligase binding

Inferred from physical interaction Ref.26. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q13546-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q13546-2)

The sequence of this isoform differs from the canonical sequence as follows:
     108-153: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 671671Receptor-interacting serine/threonine-protein kinase 1
PRO_0000086606

Regions

Domain17 – 289273Protein kinase
Domain583 – 66987Death
Nucleotide binding23 – 319ATP By similarity
Region290 – 582293Interaction with SQSTM1
Motif531 – 54717RIP homotypic interaction motif (RHIM)
Compositional bias411 – 4144Poly-Arg

Sites

Active site1381Proton acceptor By similarity
Binding site491ATP By similarity
Site324 – 3252Cleavage; by caspase-8

Amino acid modifications

Modified residue61Phosphoserine Ref.27
Modified residue201Phosphoserine; by autocatalysis Potential
Modified residue251Phosphoserine Ref.27
Modified residue1611Phosphoserine; by RIPK3 and autocatalysis Potential
Modified residue1661Phosphoserine; by autocatalysis Potential
Modified residue3031Phosphoserine Ref.27
Modified residue3201Phosphoserine Ref.27 Ref.29
Modified residue3331Phosphoserine Ref.27
Modified residue3841Phosphotyrosine Ref.18
Cross-link377Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Natural variations

Alternative sequence108 – 15346Missing in isoform 2.
VSP_037690
Natural variant641A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.39
VAR_041039
Natural variant811V → I in a colorectal adenocarcinoma sample; somatic mutation. Ref.39
VAR_041040
Natural variant2201A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.39
VAR_041041
Natural variant2341E → K. Ref.4
Corresponds to variant rs17548383 [ dbSNP | Ensembl ].
VAR_021109
Natural variant4041A → S. Ref.39
Corresponds to variant rs34872409 [ dbSNP | Ensembl ].
VAR_041042
Natural variant4381A → V. Ref.1 Ref.6 Ref.8
Corresponds to variant rs3173519 [ dbSNP | Ensembl ].
VAR_058285
Natural variant4431A → V. Ref.39
Corresponds to variant rs35722193 [ dbSNP | Ensembl ].
VAR_041043
Natural variant5691A → V. Ref.39
Corresponds to variant rs55861377 [ dbSNP | Ensembl ].
VAR_041044

Experimental info

Mutagenesis451K → A: Abolishes kinase activity. Ref.1
Mutagenesis1611S → A: Decreases RIPK1 kinase activity. Ref.27
Mutagenesis1611S → E: No effect on RIPK1 autophosphorylation. Ref.27
Mutagenesis3241D → K: Abolishes cleavage by caspase-8. Ref.9
Mutagenesis3771K → R: Abolishes RIP-mediated NF-Kappa-B activation. Ref.22
Sequence conflict2581R → I in BAG36858. Ref.3
Sequence conflict2861R → S in BAG36858. Ref.3
Sequence conflict5141T → S in AAC50137. Ref.8

Secondary structure

.................................................... 671
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 1, 2005. Version 3.
Checksum: 976E2428D525A9B2

FASTA67175,931
        10         20         30         40         50         60 
MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL 

        70         80         90        100        110        120 
LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL 

       130        140        150        160        170        180 
EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD 

       190        200        210        220        230        240 
GTAKKNGGTL YYMAPEHLND VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC 

       250        260        270        280        290        300 
IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED 

       310        320        330        340        350        360 
VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA 

       370        380        390        400        410        420 
PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF 

       430        440        450        460        470        480 
AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD 

       490        500        510        520        530        540 
PGTAGPRVWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ 

       550        560        570        580        590        600 
IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN 

       610        620        630        640        650        660 
CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID 

       670 
LLSSLIYVSQ N 

« Hide

Isoform 2 [UniParc].

Checksum: 4D3780FB4A93FDB1
Show »

FASTA62570,733

References

« Hide 'large scale' references
[1]"TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex."
Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V.
Immunity 4:387-396(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-45, INTERACTION WITH TRADD; TRAF1; TRAF2 AND TRAF3, VARIANT VAL-438.
Tissue: Umbilical vein endothelial cell.
[2]Huang J., Hsu H., Baichwal V.R., Goeddel D.V.
Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION TO 120.
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 15-671 (ISOFORM 2).
Tissue: Adrenal gland and Uterus.
[4]SeattleSNPs variation discovery resource
Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LYS-234.
[5]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT VAL-438.
[7]"Homo sapiens protein coding cDNA."
Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 153-671.
Tissue: Brain.
[8]"RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death."
Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.
Cell 81:513-523(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 300-671, VARIANT VAL-438.
Tissue: Leukemic T-cell.
[9]"Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis."
Lin Y., Devin A., Rodriguez Y., Liu Z.-G.
Genes Dev. 13:2514-2526(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY CASPASE-8, MUTAGENESIS OF ASP-324.
[10]"The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation."
Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.
EMBO J. 18:3044-3053(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SQSTM1 AND TRAF2, DOMAIN.
[11]"RIP3, a novel apoptosis-inducing kinase."
Sun X., Lee J., Navas T., Baldwin D.T., Stewart T.A., Dixit V.M.
J. Biol. Chem. 274:16871-16875(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RIPK3.
[12]"The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation."
Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., Kieff E.D.
Mol. Cell. Biol. 19:5759-5767(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BNLF1.
[13]"Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis."
Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A., Wallach D., Horwitz M.S.
Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IKBKG.
[14]"Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule."
Holler N., Zaru R., Micheau O., Thome M., Attinger A., Valitutti S., Bodmer J.L., Schneider P., Seed B., Tschopp J.
Nat. Immunol. 1:489-495(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[15]"The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome."
Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S., Vartanian T.
J. Biol. Chem. 276:8865-8874(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EGFR.
[16]"A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation."
Chen D., Li X., Zhai Z., Shu H.-B.
J. Biol. Chem. 277:15985-15991(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RNF216.
[17]"Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3."
Sun X., Yin J., Starovasnik M.A., Fairbrother W.J., Dixit V.M.
J. Biol. Chem. 277:9505-9511(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: RIP HOMOTYPIC INTERACTION MOTIF, INTERACTION WITH RIPK3.
[18]"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry."
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C.
Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[19]"ZNF216 is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation."
Huang J., Teng L., Li L., Liu T., Li L., Chen D., Xu L.-G., Zhai Z., Shu H.-B.
J. Biol. Chem. 279:16847-16853(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZFAND5.
[20]"De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling."
Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., Dixit V.M.
Nature 430:694-699(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY TRAF2, DEUBIQUITINATION BY TNFAIP3.
[21]"IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction."
Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J., Takeuchi O., Akira S.
Nat. Immunol. 6:981-988(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAVS.
[22]"Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO."
Ea C.K., Deng L., Xia Z.P., Pineda G., Chen Z.J.
Mol. Cell 22:245-257(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION AT LYS-377, MUTAGENESIS OF LYS-377.
[23]"RIP1, a kinase on the crossroads of a cell's decision to live or die."
Festjens N., Vanden Berghe T., Cornelis S., Vandenabeele P.
Cell Death Differ. 14:400-410(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[24]"RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation."
Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.
J. Biol. Chem. 282:14788-14796(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF DAB2IP, INTERACTION WITH DAB2IP.
[25]"RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation."
Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M., Chen D.Y., Zhai Z.H., Shu H.B.
J. Biol. Chem. 282:16776-16782(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RBCK1.
[26]"CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappaB activation."
Liao W., Xiao Q., Tchikov V., Fujita K., Yang W., Wincovitch S., Garfield S., Conze D., El-Deiry W.S., Schuetze S., Srinivasula S.M.
Curr. Biol. 18:641-649(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RFFL, UBIQUITINATION BY RFFL.
[27]"Identification of RIP1 kinase as a specific cellular target of necrostatins."
Degterev A., Hitomi J., Germscheid M., Ch'en I.L., Korkina O., Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M., Gerber S.A., Lugovskoy A., Yuan J.
Nat. Chem. Biol. 4:313-321(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF SER-161, INHIBITION BY NECROSTATIN-1, PHOSPHORYLATION AT SER-6; SER-20; SER-25; SER-161; SER-166; SER-303; SER-320 AND SER-333.
[28]"Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1."
Upton J.W., Kaiser W.J., Mocarski E.S.
J. Biol. Chem. 283:16966-16970(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MURID HERPESVIRUS 1 VIRAL INHIBITOR OF RIP ACTIVATION.
[29]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[30]"Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation."
Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., Chan F.K.
Cell 137:1112-1123(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION.
[31]"Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha."
He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X.
Cell 137:1100-1111(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RIPK3.
[32]"The role of the kinases RIP1 and RIP3 in TNF-induced necrosis."
Vandenabeele P., Declercq W., Van Herreweghe F., Vanden Berghe T.
Sci. Signal. 3:RE4-RE4(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[33]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[34]"Linear ubiquitination prevents inflammation and regulates immune signalling."
Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E., Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U., Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H.
Nature 471:591-596(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY THE LUBAC COMPLEX.
[35]"cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)."
Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., Gevaert K., Declercq W., Vandenabeele P.
PLoS ONE 6:E22356-E22356(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, INTERACTION WITH BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4.
[36]"The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways."
Wang Z., Jiang H., Chen S., Du F., Wang X.
Cell 148:228-243(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK3 AND MLKL.
[37]"Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1."
Zhao Y., Alonso C., Ballester I., Song J.H., Chang S.Y., Guleng B., Arihiro S., Murray P.J., Xavier R., Kobayashi K.S., Reinecker H.C.
Inflamm. Bowel Dis. 18:603-612(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARHGEF2.
[38]"Structural basis of RIP1 inhibition by necrostatins."
Xie T., Peng W., Liu Y., Yan C., Maki J., Degterev A., Yuan J., Shi Y.
Structure 21:493-499(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-294 IN COMPLEXES WITH NECROSTATIN-TYPE INHIBITORS, CATALYTIC ACTIVITY, ENZYME REGULATION, AUTOPHOSPHORYLATION.
[39]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; VAL-443 AND VAL-569.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U50062 mRNA. Translation: AAC32232.1.
AK314176 mRNA. Translation: BAG36858.1.
AK304701 mRNA. Translation: BAG65471.1. Different initiation.
AY682848 Genomic DNA. Translation: AAT74626.1.
AL031963 Genomic DNA. Translation: CAD70625.1.
BC126254 mRNA. Translation: AAI26255.1.
BC126256 mRNA. Translation: AAI26257.1.
AB208926 mRNA. Translation: BAD92163.1.
U25994 mRNA. Translation: AAC50137.1.
PIRT09479.
RefSeqNP_003795.2. NM_003804.3.
XP_005249515.1. XM_005249458.1.
UniGeneHs.519842.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4ITHX-ray2.25A/B1-294[»]
4ITIX-ray2.86A/B1-294[»]
4ITJX-ray1.80A/B1-294[»]
4NEUX-ray2.57A/B1-324[»]
ProteinModelPortalQ13546.
SMRQ13546. Positions 7-327, 579-661.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114274. 66 interactions.
DIPDIP-433N.
IntActQ13546. 31 interactions.
MINTMINT-128219.
STRING9606.ENSP00000259808.

Chemistry

BindingDBQ13546.
ChEMBLCHEMBL5464.
GuidetoPHARMACOLOGY2189.

PTM databases

PhosphoSiteQ13546.

Polymorphism databases

DMDM60393639.

Proteomic databases

PaxDbQ13546.
PRIDEQ13546.

Protocols and materials databases

DNASU8737.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000259808; ENSP00000259808; ENSG00000137275. [Q13546-1]
ENST00000380409; ENSP00000369773; ENSG00000137275. [Q13546-1]
ENST00000541791; ENSP00000442294; ENSG00000137275. [Q13546-2]
GeneID8737.
KEGGhsa:8737.
UCSCuc003muv.4. human. [Q13546-1]
uc011dhs.2. human. [Q13546-2]

Organism-specific databases

CTD8737.
GeneCardsGC06P003064.
HGNCHGNC:10019. RIPK1.
HPACAB010302.
HPA015257.
MIM603453. gene.
neXtProtNX_Q13546.
PharmGKBPA34394.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000010270.
HOVERGENHBG055612.
InParanoidQ13546.
KOK02861.
OMASHDPFAQ.
OrthoDBEOG7MPRDN.
PhylomeDBQ13546.
TreeFamTF106506.

Enzyme and pathway databases

BRENDA2.7.10.2. 2681.
ReactomeREACT_578. Apoptosis.
REACT_6900. Immune System.
SignaLinkQ13546.

Gene expression databases

BgeeQ13546.
CleanExHS_RIPK1.
GenevestigatorQ13546.

Family and domain databases

Gene3D1.10.533.10. 1 hit.
InterProIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR025735. RHIM_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00531. Death. 1 hit.
PF00069. Pkinase. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
PRINTSPR00109. TYRKINASE.
SMARTSM00005. DEATH. 1 hit.
[Graphical view]
SUPFAMSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS50017. DEATH_DOMAIN. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiRIPK1.
GenomeRNAi8737.
NextBio32775.
PMAP-CutDBQ13546.
PROQ13546.
SOURCESearch...

Entry information

Entry nameRIPK1_HUMAN
AccessionPrimary (citable) accession number: Q13546
Secondary accession number(s): A0AV89 expand/collapse secondary AC list , B2RAG1, B4E3F9, Q13180, Q59H33
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: February 1, 2005
Last modified: April 16, 2014
This is version 153 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM