ID RIPK1_HUMAN Reviewed; 671 AA. AC Q13546; A0AV89; Q13180; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-2005, sequence version 3. DT 26-MAY-2009, entry version 94. DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 1; DE EC=2.7.11.1; DE AltName: Full=Serine/threonine-protein kinase RIP; DE AltName: Full=Cell death protein RIP; DE AltName: Full=Receptor-interacting protein; GN Name=RIPK1; Synonyms=RIP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AUTOPHOSPHORYLATION, MUTAGENESIS OF RP LYS-45, AND INTERACTION WITH TRADD; TRAF1; TRAF2 AND TRAF3. RC TISSUE=Umbilical vein endothelial cell; RX MEDLINE=96200892; PubMed=8612133; DOI=10.1016/S1074-7613(00)80252-6; RA Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V.; RT "TNF-dependent recruitment of the protein kinase RIP to the TNF RT receptor-1 signaling complex."; RL Immunity 4:387-396(1996). RN [2] RP SEQUENCE REVISION TO 120. RA Huang J., Hsu H., Baichwal V.R., Goeddel D.V.; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-234. RG SeattleSNPs variation discovery resource; RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX MEDLINE=22935763; PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S., RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., RA Frankland J., French L., Garner P., Garnett J., Ghori M.J., RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 300-671. RC TISSUE=Leukemic T-cell; RX MEDLINE=95277838; PubMed=7538908; DOI=10.1016/0092-8674(95)90072-1; RA Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.; RT "RIP: a novel protein containing a death domain that interacts with RT Fas/APO-1 (CD95) in yeast and causes cell death."; RL Cell 81:513-523(1995). RN [7] RP CLEAVAGE BY CASPASE-8, AND MUTAGENESIS OF ASP-324. RX MEDLINE=99452794; PubMed=10521396; DOI=10.1101/gad.13.19.2514; RA Lin Y., Devin A., Rodriguez Y., Liu Z.-G.; RT "Cleavage of the death domain kinase RIP by caspase-8 prompts TNF- RT induced apoptosis."; RL Genes Dev. 13:2514-2526(1999). RN [8] RP INTERACTION WITH SQSTM1 AND TRAF2, AND DOMAIN. RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044; RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.; RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB RT activation."; RL EMBO J. 18:3044-3053(1999). RN [9] RP INTERACTION WITH RIPK3. RX MEDLINE=99287880; PubMed=10358032; DOI=10.1074/jbc.274.24.16871; RA Sun X., Lee J., Navas T., Baldwin D.T., Stewart T.A., Dixit V.M.; RT "RIP3, a novel apoptosis-inducing kinase."; RL J. Biol. Chem. 274:16871-16875(1999). RN [10] RP INTERACTION WITH BNLF1. RX MEDLINE=99340272; PubMed=10409763; RA Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., RA Kieff E.D.; RT "The Epstein-Barr virus oncoprotein latent membrane protein 1 engages RT the tumor necrosis factor receptor-associated proteins TRADD and RT receptor-interacting protein (RIP) but does not induce apoptosis or RT require RIP for NF-kappaB activation."; RL Mol. Cell. Biol. 19:5759-5767(1999). RN [11] RP INTERACTION WITH IKBKG. RX MEDLINE=99128359; PubMed=9927690; DOI=10.1073/pnas.96.3.1042; RA Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A., RA Wallach D., Horwitz M.S.; RT "Identification of a cell protein (FIP-3) as a modulator of NF-kappaB RT activity and as a target of an adenovirus inhibitor of tumor necrosis RT factor alpha-induced apoptosis."; RL Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999). RN [12] RP INTERACTION WITH EGFR. RX MEDLINE=21153697; PubMed=11116146; DOI=10.1074/jbc.M008458200; RA Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S., RA Vartanian T.; RT "The epidermal growth factor receptor engages receptor interacting RT protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to RT activate NF-kappa B. Identification of a novel receptor-tyrosine RT kinase signalosome."; RL J. Biol. Chem. 276:8865-8874(2001). RN [13] RP INTERACTION WITH UBCE7IP1. RX MEDLINE=21975204; PubMed=11854271; DOI=10.1074/jbc.M108675200; RA Chen D., Li X., Zhai Z., Shu H.-B.; RT "A novel zinc finger protein interacts with receptor-interacting RT protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1- RT induced NF-kappa B activation."; RL J. Biol. Chem. 277:15985-15991(2002). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384; TYR-387 AND RP SER-389, AND MASS SPECTROMETRY. RC TISSUE=T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites RT from human T cells using immobilized metal affinity chromatography and RT tandem mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [15] RP INTERACTION WITH MAVS. RX PubMed=16127453; DOI=10.1038/ni1243; RA Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., RA Ishii K.J., Takeuchi O., Akira S.; RT "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I RT interferon induction."; RL Nat. Immunol. 6:981-988(2005). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND MASS RP SPECTROMETRY. RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [17] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; RP VAL-443 AND VAL-569. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Promotes apoptosis and activation of NF-kappa-B. CC Required for TNFRSF1A mediated activation of NF-kappa-B. CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CC -!- SUBUNIT: Binds to the death domain of TNFRSF6 and TRADD. Is CC recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds CC RIPK3, UBCE7IP1 isoform 3 (ZIN), EGFR, IKBKG, TRAF1, TRAF2 and CC TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha CC stimulation. May interacts with MAVS/IPS1. CC -!- INTERACTION: CC Q14790:CASP8; NbExp=1; IntAct=EBI-358507, EBI-78060; CC Q8IVM0:CCDC50; NbExp=2; IntAct=EBI-358507, EBI-723996; CC P48729:CSNK1A1; NbExp=4; IntAct=EBI-358507, EBI-1383726; CC Q9Y6K9:IKBKG; NbExp=1; IntAct=EBI-358507, EBI-81279; CC Q07174:Map3k8 (xeno); NbExp=1; IntAct=EBI-358507, EBI-309771; CC P25799:Nfkb1 (xeno); NbExp=1; IntAct=EBI-358507, EBI-643958; CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- PTM: Proteolytically cleaved by caspase-8 during TNF-induced CC apoptosis. Cleavage abolishes NF-kappa-B activation and enhances CC pro-apototic signaling through the TRADD-FADD interaction. CC -!- PTM: Autophosphorylated on serine and threonine residues. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. CC -!- SIMILARITY: Contains 1 death domain. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/ripk1/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U50062; AAC32232.1; -; mRNA. DR EMBL; AY682848; AAT74626.1; -; Genomic_DNA. DR EMBL; AL031963; CAD70625.1; -; Genomic_DNA. DR EMBL; BC126254; AAI26255.1; -; mRNA. DR EMBL; BC126256; AAI26257.1; -; mRNA. DR EMBL; U25994; AAC50137.1; -; mRNA. DR IPI; IPI00013773; -. DR PIR; T09479; T09479. DR RefSeq; NP_003795.2; -. DR UniGene; Hs.519842; -. DR HSSP; P41240; 1BYG. DR DIP; DIP:433N; -. DR IntAct; Q13546; 27. DR PhosphoSite; Q13546; -. DR PRIDE; Q13546; -. DR Ensembl; ENSG00000137275; Homo sapiens. DR GeneID; 8737; -. DR KEGG; hsa:8737; -. DR GeneCards; GC06P003022; -. DR H-InvDB; HIX0005535; -. DR HGNC; HGNC:10019; RIPK1. DR HPA; CAB010302; -. DR HPA; HPA015257; -. DR MIM; 603453; gene. DR PharmGKB; PA34394; -. DR HOGENOM; Q13546; -. DR HOVERGEN; Q13546; -. DR OMA; Q13546; SHDPFAQ. DR BRENDA; 2.7.10.2; 247. DR BRENDA; 2.7.11.1; 247. DR Pathway_Interaction_DB; caspase_pathway; Caspase cascade in apoptosis. DR Pathway_Interaction_DB; ceramidepathway; Ceramide signaling pathway. DR Pathway_Interaction_DB; faspathway; FAS signaling pathway (CD95). DR Pathway_Interaction_DB; hivnefpathway; HIV-1 Nef: Negative effector of Fas and TNF-alpha. DR Pathway_Interaction_DB; p38alphabetapathway; Regulation of p38-alpha and p38-beta. DR Pathway_Interaction_DB; tnfpathway; TNF receptor signaling pathway. DR Pathway_Interaction_DB; trail_pathway; TRAIL signaling pathway. DR Reactome; REACT_578; Apoptosis. DR Reactome; REACT_6900; Signaling in Immune system. DR NextBio; 32775; -. DR PMAP-CutDB; Q13546; -. DR ArrayExpress; Q13546; -. DR Bgee; Q13546; -. DR CleanEx; HS_RIPK1; -. DR GO; GO:0005829; C:cytosol; EXP:Reactome. DR GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0043235; C:receptor complex; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0070513; F:death domain binding; IPI:UniProtKB. DR GO; GO:0005123; F:death receptor binding; IPI:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:InterPro. DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:InterPro. DR GO; GO:0007257; P:activation of JUN kinase activity; TAS:UniProtKB. DR GO; GO:0008633; P:activation of pro-apoptotic gene products; EXP:Reactome. DR GO; GO:0006917; P:induction of apoptosis; IMP:UniProtKB. DR GO; GO:0045768; P:positive regulation of anti-apoptosis; TAS:UniProtKB. DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-k...; IEP:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcript...; IMP:UniProtKB. DR GO; GO:0046777; P:protein amino acid autophosphorylation; IDA:UniProtKB. DR GO; GO:0080010; P:regulation of oxygen and reactive oxygen sp...; TAS:UniProtKB. DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:UniProtKB. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pa...; IC:UniProtKB. DR InterPro; IPR000488; Death. DR InterPro; IPR011029; DEATH_like. DR InterPro; IPR000719; Prot_kinase_core. DR InterPro; IPR017442; Se/Thr_pkinase-rel. DR InterPro; IPR008271; Ser_thr_pkin_AS. DR InterPro; IPR001245; Tyr_pkinase. DR Gene3D; G3DSA:1.10.533.10; DEATH_like; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF00069; Pkinase; 1. DR PRINTS; PR00109; TYRKINASE. DR ProDom; PD000001; Prot_kinase; 1. DR SMART; SM00005; DEATH; 1. DR PROSITE; PS50017; DEATH_DOMAIN; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW Apoptosis; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; KW Phosphoprotein; Polymorphism; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1 671 Receptor-interacting serine/threonine- FT protein kinase 1. FT /FTId=PRO_0000086606. FT DOMAIN 17 289 Protein kinase. FT DOMAIN 583 669 Death. FT NP_BIND 23 31 ATP (By similarity). FT REGION 290 582 Interaction with SQSTM1. FT COMPBIAS 411 414 Poly-Arg. FT ACT_SITE 138 138 Proton acceptor (By similarity). FT BINDING 49 49 ATP (By similarity). FT SITE 324 325 Cleavage; by caspase-8. FT MOD_RES 320 320 Phosphoserine. FT MOD_RES 384 384 Phosphotyrosine. FT MOD_RES 387 387 Phosphotyrosine. FT MOD_RES 389 389 Phosphoserine. FT VARIANT 64 64 A -> V (in a colorectal adenocarcinoma FT sample; somatic mutation). FT /FTId=VAR_041039. FT VARIANT 81 81 V -> I (in a colorectal adenocarcinoma FT sample; somatic mutation). FT /FTId=VAR_041040. FT VARIANT 220 220 A -> V (in a colorectal adenocarcinoma FT sample; somatic mutation). FT /FTId=VAR_041041. FT VARIANT 234 234 E -> K (in dbSNP:rs17548383). FT /FTId=VAR_021109. FT VARIANT 404 404 A -> S. FT /FTId=VAR_041042. FT VARIANT 443 443 A -> V. FT /FTId=VAR_041043. FT VARIANT 569 569 A -> V. FT /FTId=VAR_041044. FT MUTAGEN 45 45 K->A: Abolishes kinase activity. FT MUTAGEN 324 324 D->K: Abolishes cleavage by caspase-8. FT CONFLICT 438 438 A -> V (in Ref. 1 and 6). FT CONFLICT 514 514 T -> S (in Ref. 6; AAC50137). SQ SEQUENCE 671 AA; 75931 MW; 976E2428D525A9B2 CRC64; MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD GTAKKNGGTL YYMAPEHLND VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD PGTAGPRVWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID LLSSLIYVSQ N //