ID RIPK1_HUMAN Reviewed; 671 AA. AC Q13546; A0AV89; B2RAG1; B4E3F9; Q13180; Q59H33; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-2005, sequence version 3. DT 27-MAR-2024, entry version 235. DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 1; DE EC=2.7.11.1 {ECO:0000269|PubMed:23473668, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:8612133}; DE AltName: Full=Cell death protein RIP {ECO:0000303|PubMed:8612133}; DE AltName: Full=Receptor-interacting protein 1 {ECO:0000303|PubMed:16603398}; DE Short=RIP-1 {ECO:0000303|PubMed:16603398}; GN Name=RIPK1 {ECO:0000312|HGNC:HGNC:10019}; GN Synonyms=RIP {ECO:0000303|PubMed:8612133}, RIP1 GN {ECO:0000303|PubMed:16603398}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, RP AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-45, INTERACTION WITH TRADD; TRAF1; RP TRAF2 AND TRAF3, AND VARIANT VAL-438. RC TISSUE=Umbilical vein endothelial cell; RX 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 receptor-1 RT 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 [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 15-671 (ISOFORM 2). RC TISSUE=Adrenal gland, and Uterus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX 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., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., 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., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-438. 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 153-671. RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RT "Homo sapiens protein coding cDNA."; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 300-671, AND VARIANT VAL-438. RC TISSUE=Leukemic T-cell; RX 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 [9] RP INTERACTION WITH CRADD, AND DOMAIN. RX PubMed=9044836; RA Ahmad M., Srinivasula S.M., Wang L., Talanian R.V., Litwack G., RA Fernandes-Alnemri T., Alnemri E.S.; RT "CRADD, a novel human apoptotic adaptor molecule for caspase-2, and RT FasL/tumor necrosis factor receptor-interacting protein RIP."; RL Cancer Res. 57:615-619(1997). RN [10] RP CLEAVAGE BY CASP8, AND MUTAGENESIS OF ASP-324. RX 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-induced RT apoptosis."; RL Genes Dev. 13:2514-2526(1999). RN [11] RP INTERACTION WITH SQSTM1 AND TRAF2, AND DOMAIN DEATH. 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 [12] RP INTERACTION WITH RIPK3. RX 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 [13] RP INTERACTION WITH BNLF1. RX PubMed=10409763; DOI=10.1128/mcb.19.8.5759; RA Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., Kieff E.D.; RT "The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the RT tumor necrosis factor receptor-associated proteins TRADD and receptor- RT interacting protein (RIP) but does not induce apoptosis or require RIP for RT NF-kappaB activation."; RL Mol. Cell. Biol. 19:5759-5767(1999). RN [14] RP INTERACTION WITH IKBKG. RX 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 [15] RP FUNCTION. RX PubMed=11101870; DOI=10.1038/82732; RA Holler N., Zaru R., Micheau O., Thome M., Attinger A., Valitutti S., RA Bodmer J.L., Schneider P., Seed B., Tschopp J.; RT "Fas triggers an alternative, caspase-8-independent cell death pathway RT using the kinase RIP as effector molecule."; RL Nat. Immunol. 1:489-495(2000). RN [16] RP INTERACTION WITH EGFR. RX 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 protein RT and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF- RT kappa B. Identification of a novel receptor-tyrosine kinase signalosome."; RL J. Biol. Chem. 276:8865-8874(2001). RN [17] RP INTERACTION WITH RNF216. RX 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 protein RT (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B RT activation."; RL J. Biol. Chem. 277:15985-15991(2002). RN [18] RP RIP HOMOTYPIC INTERACTION MOTIF, AND INTERACTION WITH RIPK3. RX PubMed=11734559; DOI=10.1074/jbc.m109488200; RA Sun X., Yin J., Starovasnik M.A., Fairbrother W.J., Dixit V.M.; RT "Identification of a novel homotypic interaction motif required for the RT phosphorylation of receptor-interacting protein (RIP) by RIP3."; RL J. Biol. Chem. 277:9505-9511(2002). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic 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 from RT human T cells using immobilized metal affinity chromatography and tandem RT mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [20] RP INTERACTION WITH ZFAND5. RX PubMed=14754897; DOI=10.1074/jbc.m309491200; RA Huang J., Teng L., Li L., Liu T., Li L., Chen D., Xu L.-G., Zhai Z., RA Shu H.-B.; RT "ZNF216 is an A20-like and IkappaB kinase gamma-interacting inhibitor of RT NFkappaB activation."; RL J. Biol. Chem. 279:16847-16853(2004). RN [21] RP INTERACTION WITH DAB2IP. RX PubMed=15310755; DOI=10.1074/jbc.m407617200; RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.; RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2- RT induced ASK1-JNK activation."; RL J. Biol. Chem. 279:44955-44965(2004). RN [22] RP UBIQUITINATION BY TRAF2, AND DEUBIQUITINATION BY TNFAIP3. RX PubMed=15258597; DOI=10.1038/nature02794; RA Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., RA Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., Dixit V.M.; RT "De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF- RT kappaB signalling."; RL Nature 430:694-699(2004). RN [23] RP INTERACTION WITH MAVS. RX PubMed=16127453; DOI=10.1038/ni1243; RA Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J., RA Takeuchi O., Akira S.; RT "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon RT induction."; RL Nat. Immunol. 6:981-988(2005). RN [24] RP UBIQUITINATION AT LYS-377, AND MUTAGENESIS OF LYS-377. RX PubMed=16603398; DOI=10.1016/j.molcel.2006.03.026; RA Ea C.K., Deng L., Xia Z.P., Pineda G., Chen Z.J.; RT "Activation of IKK by TNFalpha requires site-specific ubiquitination of RT RIP1 and polyubiquitin binding by NEMO."; RL Mol. Cell 22:245-257(2006). RN [25] RP INTERACTION WITH TAX1BP1, FUNCTION, AND UBIQUITINATION. RX PubMed=17703191; DOI=10.1038/sj.emboj.7601823; RA Shembade N., Harhaj N.S., Liebl D.J., Harhaj E.W.; RT "Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and RT LPS-mediated NF-kappaB and JNK signaling."; RL EMBO J. 26:3910-3922(2007). RN [26] RP REVIEW. RX PubMed=17301840; DOI=10.1038/sj.cdd.4402085; RA Festjens N., Vanden Berghe T., Cornelis S., Vandenabeele P.; RT "RIP1, a kinase on the crossroads of a cell's decision to live or die."; RL Cell Death Differ. 14:400-410(2007). RN [27] RP FUNCTION IN PHOSPHORYLATION OF DAB2IP, AND INTERACTION WITH DAB2IP. RX PubMed=17389591; DOI=10.1074/jbc.m701148200; RA Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.; RT "RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical RT for tumor necrosis factor-induced ASK1-JNK/p38 activation."; RL J. Biol. Chem. 282:14788-14796(2007). RN [28] RP INTERACTION WITH RBCK1. RX PubMed=17449468; DOI=10.1074/jbc.m701913200; RA Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M., RA Chen D.Y., Zhai Z.H., Shu H.B.; RT "RBCK1 negatively regulates tumor necrosis factor- and interleukin-1- RT triggered NF-kappaB activation by targeting TAB2/3 for degradation."; RL J. Biol. Chem. 282:16776-16782(2007). RN [29] RP INTERACTION WITH RFFL, AND UBIQUITINATION BY RFFL. RX PubMed=18450452; DOI=10.1016/j.cub.2008.04.017; RA Liao W., Xiao Q., Tchikov V., Fujita K., Yang W., Wincovitch S., RA Garfield S., Conze D., El-Deiry W.S., Schuetze S., Srinivasula S.M.; RT "CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates RT TNF-induced NF-kappaB activation."; RL Curr. Biol. 18:641-649(2008). RN [30] RP MUTAGENESIS OF SER-161, INHIBITION BY NECROSTATIN-1, AND PHOSPHORYLATION AT RP SER-6; SER-20; SER-25; SER-161; SER-166; SER-303; SER-320 AND SER-333. RX PubMed=18408713; DOI=10.1038/nchembio.83; RA Degterev A., Hitomi J., Germscheid M., Ch'en I.L., Korkina O., Teng X., RA Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M., Gerber S.A., RA Lugovskoy A., Yuan J.; RT "Identification of RIP1 kinase as a specific cellular target of RT necrostatins."; RL Nat. Chem. Biol. 4:313-321(2008). RN [31] RP INTERACTION WITH MURID HERPESVIRUS 1 PROTEIN RIR1. RX PubMed=18442983; DOI=10.1074/jbc.c800051200; RA Upton J.W., Kaiser W.J., Mocarski E.S.; RT "Cytomegalovirus M45 cell death suppression requires receptor-interacting RT protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RT RIP1."; RL J. Biol. Chem. 283:16966-16970(2008). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; 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 [33] RP FUNCTION, AND PHOSPHORYLATION. RX PubMed=19524513; DOI=10.1016/j.cell.2009.05.037; RA Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., RA Chan F.K.; RT "Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates RT programmed necrosis and virus-induced inflammation."; RL Cell 137:1112-1123(2009). RN [34] RP FUNCTION, AND INTERACTION WITH RIPK3. RX PubMed=19524512; DOI=10.1016/j.cell.2009.05.021; RA He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X.; RT "Receptor interacting protein kinase-3 determines cellular necrotic RT response to TNF-alpha."; RL Cell 137:1100-1111(2009). RN [35] RP INTERACTION WITH RNF34, AND UBIQUITINATION BY RNF34. RX DOI=10.1016/j.cub.2008.11.041; RA Liao W., Fujita K., Xiao Q., Tchikov V., Yang W., Gunsor M., Garfield S., RA Goldsmith P., El-Deiry W.S., Schuetze S., Srinivasula S.M.; RT "Response: CARP1 regulates induction of NF-kappaB by TNFalpha."; RL Curr. Biol. 19:R17-R19(2009). RN [36] RP REVIEW. RX PubMed=20354226; DOI=10.1126/scisignal.3115re4; RA Vandenabeele P., Declercq W., Van Herreweghe F., Vanden Berghe T.; RT "The role of the kinases RIP1 and RIP3 in TNF-induced necrosis."; RL Sci. Signal. 3:RE4-RE4(2010). RN [37] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [38] RP UBIQUITINATION BY THE LUBAC COMPLEX. RX PubMed=21455173; DOI=10.1038/nature09816; RA Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E., RA Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U., RA Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H.; RT "Linear ubiquitination prevents inflammation and regulates immune RT signalling."; RL Nature 471:591-596(2011). RN [39] RP UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, AND INTERACTION WITH RP BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4. RX PubMed=21931591; DOI=10.1371/journal.pone.0022356; RA Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., RA Gevaert K., Declercq W., Vandenabeele P.; RT "cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin RT chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)."; RL PLoS ONE 6:E22356-E22356(2011). RN [40] RP IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK3 AND MLKL. RX PubMed=22265414; DOI=10.1016/j.cell.2011.11.030; RA Wang Z., Jiang H., Chen S., Du F., Wang X.; RT "The mitochondrial phosphatase PGAM5 functions at the convergence point of RT multiple necrotic death pathways."; RL Cell 148:228-243(2012). RN [41] RP INTERACTION WITH ARHGEF2. RX PubMed=21887730; DOI=10.1002/ibd.21851; RA Zhao Y., Alonso C., Ballester I., Song J.H., Chang S.Y., Guleng B., RA Arihiro S., Murray P.J., Xavier R., Kobayashi K.S., Reinecker H.C.; RT "Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1."; RL Inflamm. Bowel Dis. 18:603-612(2012). RN [42] RP PROTEOLYTIC CLEAVAGE. RX PubMed=22858542; DOI=10.1038/cdd.2012.98; RA van Raam B.J., Ehrnhoefer D.E., Hayden M.R., Salvesen G.S.; RT "Intrinsic cleavage of receptor-interacting protein kinase-1 by RT caspase-6."; RL Cell Death Differ. 20:86-96(2013). RN [43] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [44] RP FUNCTION, AND DEUBIQUITINATION BY USP7. RX PubMed=24144979; DOI=10.1128/mcb.00465-13; RA Zaman M.M., Nomura T., Takagi T., Okamura T., Jin W., Shinagawa T., RA Tanaka Y., Ishii S.; RT "Ubiquitination-deubiquitination by the TRIM27-USP7 complex regulates tumor RT necrosis factor alpha-induced apoptosis."; RL Mol. Cell. Biol. 33:4971-4984(2013). RN [45] RP GLYCOSYLATION AT ARG-603 (MICROBIAL INFECTION). RX PubMed=23955153; DOI=10.1038/nature12436; RA Li S., Zhang L., Yao Q., Li L., Dong N., Rong J., Gao W., Ding X., Sun L., RA Chen X., Chen S., Shao F.; RT "Pathogen blocks host death receptor signalling by arginine GlcNAcylation RT of death domains."; RL Nature 501:242-246(2013). RN [46] RP INTERACTION WITH TNFRSF1A. RX PubMed=24130170; DOI=10.1093/carcin/bgt338; RA Kim T.W., Kang Y.K., Park Z.Y., Kim Y.H., Hong S.W., Oh S.J., Sohn H.A., RA Yang S.J., Jang Y.J., Lee D.C., Kim S.Y., Yoo H.S., Kim E., Yeom Y.I., RA Park K.C.; RT "SH3RF2 functions as an oncogene by mediating PAK4 protein stability."; RL Carcinogenesis 35:624-634(2014). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [48] RP REVIEW. RX PubMed=25459879; DOI=10.1016/j.molcel.2014.11.001; RA Weinlich R., Green D.R.; RT "The two faces of receptor interacting protein kinase-1."; RL Mol. Cell 56:469-480(2014). RN [49] RP INTERACTION WITH TICAM1. RX PubMed=25736436; DOI=10.15252/embr.201439637; RA Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B., RA Liu Y.; RT "WDFY1 mediates TLR3/4 signaling by recruiting TRIF."; RL EMBO Rep. 16:447-455(2015). RN [50] RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 AND 2 PROTEIN RIR1 (MICROBIAL RP INFECTION). RX PubMed=25674983; DOI=10.1016/j.chom.2015.01.003; RA Guo H., Omoto S., Harris P.A., Finger J.N., Bertin J., Gough P.J., RA Kaiser W.J., Mocarski E.S.; RT "Herpes simplex virus suppresses necroptosis in human cells."; RL Cell Host Microbe 17:243-251(2015). RN [51] RP INTERACTION WITH MUMPS VIRUS PROTEIN SH (MICROBIAL INFECTION). RX PubMed=28659487; DOI=10.1128/jvi.01037-17; RA Franz S., Rennert P., Woznik M., Gruetzke J., Luedde A., Arriero Pais E.M., RA Finsterbusch T., Geyer H., Mankertz A., Friedrich N.; RT "Mumps virus SH protein inhibits NF-kappaB activation by interacting with RT tumor necrosis factor receptor 1, interleukin-1 receptor 1, and Toll-like RT receptor 3 complexes."; RL J. Virol. 91:0-0(2017). RN [52] RP INTERACTION WITH PELI1 AND RIPK3, AND UBIQUITINATION BY PELI1. RX PubMed=29883609; DOI=10.1016/j.molcel.2018.05.016; RA Choi S.W., Park H.H., Kim S., Chung J.M., Noh H.J., Kim S.K., Song H.K., RA Lee C.W., Morgan M.J., Kang H.C., Kim Y.S.; RT "PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent RT proteasomal degradation."; RL Mol. Cell 70:920-935(2018). RN [53] RP FUNCTION, SUBUNIT, MUTAGENESIS OF LYS-599, AND PHOSPHORYLATION AT SER-166. RX PubMed=29440439; DOI=10.1073/pnas.1722013115; RA Meng H., Liu Z., Li X., Wang H., Jin T., Wu G., Shan B., RA Christofferson D.E., Qi C., Yu Q., Li Y., Yuan J.; RT "Death-domain dimerization-mediated activation of RIPK1 controls RT necroptosis and RIPK1-dependent apoptosis."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E2001-E2009(2018). RN [54] RP INVOLVEMENT IN IMD57. RX PubMed=30026316; DOI=10.1126/science.aar2641; RA Cuchet-Lourenco D., Eletto D., Wu C., Plagnol V., Papapietro O., Curtis J., RA Ceron-Gutierrez L., Bacon C.M., Hackett S., Alsaleem B., Maes M., RA Gaspar M., Alisaac A., Goss E., AlIdrissi E., Siegmund D., Wajant H., RA Kumararatne D., AlZahrani M.S., Arkwright P.D., Abinun M., Doffinger R., RA Nejentsev S.; RT "Biallelic RIPK1 mutations in humans cause severe immunodeficiency, RT arthritis, and intestinal inflammation."; RL Science 361:810-813(2018). RN [55] RP REVIEW. RX PubMed=31457011; DOI=10.3389/fcell.2019.00163; RA Ang R.L., Chan M., Ting A.T.; RT "Ripoptocide - A Spark for Inflammation."; RL Front. Cell Dev. Biol. 7:163-163(2019). RN [56] RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-25, AND MUTAGENESIS OF RP SER-25 AND LYS-45. RX PubMed=30988283; DOI=10.1038/s41467-019-09690-0; RA Dondelinger Y., Delanghe T., Priem D., Wynosky-Dolfi M.A., Sorobetea D., RA Rojas-Rivera D., Giansanti P., Roelandt R., Gropengiesser J., RA Ruckdeschel K., Savvides S.N., Heck A.J.R., Vandenabeele P., Brodsky I.E., RA Bertrand M.J.M.; RT "Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in RT models of infection and inflammation."; RL Nat. Commun. 10:1729-1729(2019). RN [57] RP FUNCTION, PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION), AND MUTAGENESIS OF RP 539-ILE--GLY-542. RX PubMed=32657447; DOI=10.15252/embj.2020104469; RA Ashida H., Sasakawa C., Suzuki T.; RT "A unique bacterial tactic to circumvent the cell death crosstalk induced RT by blockade of caspase-8."; RL EMBO J. 39:e104469-e104469(2020). RN [58] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-294 IN COMPLEXES WITH RP NECROSTATIN-TYPE INHIBITORS, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND RP AUTOPHOSPHORYLATION. RX PubMed=23473668; DOI=10.1016/j.str.2013.01.016; RA Xie T., Peng W., Liu Y., Yan C., Maki J., Degterev A., Yuan J., Shi Y.; RT "Structural basis of RIP1 inhibition by necrostatins."; RL Structure 21:493-499(2013). RN [59] {ECO:0007744|PDB:5V7Z} RP STRUCTURE BY NMR OF 532-549 IN COMPLEX WITH RIPK3, SUBUNIT, INTERACTION RP WITH RIPK3, DOMAIN, AND MUTAGENESIS OF SER-536. RX PubMed=29681455; DOI=10.1016/j.cell.2018.03.032; RA Mompean M., Li W., Li J., Laage S., Siemer A.B., Bozkurt G., Wu H., RA McDermott A.E.; RT "The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid RT signaling complex."; RL Cell 173:1244-1253(2018). RN [60] {ECO:0007744|PDB:6AC5} RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 561-671, GLYCOSYLATION AT ARG-603 RP (MICROBIAL INFECTION), AND MUTAGENESIS OF ARG-603. RX PubMed=30979585; DOI=10.1016/j.molcel.2019.03.028; RA Ding J., Pan X., Du L., Yao Q., Xue J., Yao H., Wang D.C., Li S., Shao F.; RT "Structural and functional insights into host death domains inactivation by RT the bacterial arginine GlcNAcyltransferase effector."; RL Mol. Cell 74:922-935(2019). RN [61] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; VAL-443 RP AND VAL-569. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [62] RP INVOLVEMENT IN AIEFL, VARIANTS AIEFL ASN-324; HIS-324 AND TYR-324, RP CHARACTERIZATION OF VARIANTS AIEFL ASN-324; HIS-324 AND TYR-324, CLEAVAGE RP BY CASP8, AND FUNCTION. RX PubMed=31827281; DOI=10.1038/s41586-019-1828-5; RA Lalaoui N., Boyden S.E., Oda H., Wood G.M., Stone D.L., Chau D., Liu L., RA Stoffels M., Kratina T., Lawlor K.E., Zaal K.J.M., Hoffmann P.M., RA Etemadi N., Shield-Artin K., Biben C., Tsai W.L., Blake M.D., Kuehn H.S., RA Yang D., Anderton H., Silke N., Wachsmuth L., Zheng L., Moura N.S., RA Beck D.B., Gutierrez-Cruz G., Ombrello A.K., Pinto-Patarroyo G.P., RA Kueh A.J., Herold M.J., Hall C., Wang H., Chae J.J., Dmitrieva N.I., RA McKenzie M., Light A., Barham B.K., Jones A., Romeo T.M., Zhou Q., RA Aksentijevich I., Mullikin J.C., Gross A.J., Shum A.K., Hawkins E.D., RA Masters S.L., Lenardo M.J., Boehm M., Rosenzweig S.D., Pasparakis M., RA Voss A.K., Gadina M., Kastner D.L., Silke J.; RT "Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory RT disease."; RL Nature 577:103-108(2020). RN [63] RP INVOLVEMENT IN AIEFL, VARIANTS AIEFL HIS-324 AND VAL-324, CHARACTERIZATION RP OF VARIANTS AIEFL HIS-324 AND VAL-324, FUNCTION, CATALYTIC ACTIVITY, RP AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-166, AND CLEAVAGE BY CASP8. RX PubMed=31827280; DOI=10.1038/s41586-019-1830-y; RA Tao P., Sun J., Wu Z., Wang S., Wang J., Li W., Pan H., Bai R., Zhang J., RA Wang Y., Lee P.Y., Ying W., Zhou Q., Hou J., Wang W., Sun B., Yang M., RA Liu D., Fang R., Han H., Yang Z., Huang X., Li H., Deuitch N., Zhang Y., RA Dissanayake D., Haude K., McWalter K., Roadhouse C., MacKenzie J.J., RA Laxer R.M., Aksentijevich I., Yu X., Wang X., Yuan J., Zhou Q.; RT "A dominant autoinflammatory disease caused by non-cleavable variants of RT RIPK1."; RL Nature 577:109-114(2020). CC -!- FUNCTION: Serine-threonine kinase which is a key regulator of TNF- CC mediated apoptosis, necroptosis and inflammatory pathways CC (PubMed:32657447, PubMed:31827280, PubMed:31827281, PubMed:17703191, CC PubMed:24144979). Exhibits kinase activity-dependent functions that CC regulate cell death and kinase-independent scaffold functions CC regulating inflammatory signaling and cell survival (PubMed:11101870, CC PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). CC Has kinase-independent scaffold functions: upon binding of TNF to CC TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also CC known as complex I) where it acts as a scaffold protein promoting cell CC survival, in part, by activating the canonical NF-kappa-B pathway (By CC similarity). Kinase activity is essential to regulate necroptosis and CC apoptosis, two parallel forms of cell death: upon activation of its CC protein kinase activity, regulates assembly of two death-inducing CC complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives CC apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives CC necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent CC TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 CC acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated CC by RIPK3 component of complex IIb, which catalyzes phosphorylation of CC MLKL upon induction by ZBP1 (PubMed:19524512, PubMed:19524513, CC PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis CC via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits CC TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, CC PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and CC necroptosis during embryonic development: acts by preventing the CC interaction of TRADD with FADD thereby limiting aberrant activation of CC CASP8 (By similarity). In addition to apoptosis and necroptosis, also CC involved in inflammatory response by promoting transcriptional CC production of pro-inflammatory cytokines, such as interleukin-6 (IL6) CC (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and CC RIPK3 undergo reciprocal auto- and trans-phosphorylation CC (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha- CC dependent manner, and thereby activates the MAP3K5-JNK apoptotic CC cascade (PubMed:17389591, PubMed:15310755). Required for ZBP1-induced CC NF-kappa-B activation in response to DNA damage (By similarity). CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:11101870, CC ECO:0000269|PubMed:15310755, ECO:0000269|PubMed:17389591, CC ECO:0000269|PubMed:17703191, ECO:0000269|PubMed:19524512, CC ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:24144979, CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30988283, CC ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281, CC ECO:0000269|PubMed:32657447}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:23473668, ECO:0000269|PubMed:30988283, CC ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:8612133}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:23473668, CC ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280, CC ECO:0000269|PubMed:8612133}; CC -!- ACTIVITY REGULATION: Serine-threonine kinase activity is inhibited by CC linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By CC similarity). Inhibited by necrostatins, including necrostatin-1, CC necrostatin-3 and necrostatin-4 (PubMed:23473668). CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:23473668}. CC -!- SUBUNIT: Homodimer (PubMed:29440439, PubMed:29681455). Interacts (via CC RIP homotypic interaction motif) with RIPK3 (via RIP homotypic CC interaction motif); this interaction induces RIPK1 phosphorylation and CC formation of a RIPK1-RIPK3 necroptosis-inducing complex CC (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032, CC PubMed:29681455). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer CC further interacts with PGAM5 and MLKL; the formation of this complex CC leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase CC activity (PubMed:22265414). Interacts (via the death domain) with CC TNFRSF6 (via the death domain) and TRADD (via the death domain) CC (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent CC process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and CC TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, CC PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts CC with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact CC with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5 CC (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts CC with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 CC and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with CC DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha- CC dependent manner (PubMed:17389591, PubMed:15310755). Interacts with CC ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with CC RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts CC with RNF34; involved in RIPK1 ubiquitination (Ref.35). Interacts with CC TICAM1 and this interaction is enhanced in the presence of WDFY1 CC (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts CC (via death domain) with CRADD (via death domain); the interaction is CC direct (PubMed:9044836). Component of complex IIa composed of at least CC RIPK1, FADD and CASP8 (By similarity). Component of the AIM2 CC PANoptosome complex, a multiprotein complex that drives inflammatory CC cell death (PANoptosis) (By similarity). Interacts with MAP3K7, CFLAR, CC CASP8, FADD and NEMO (By similarity). Interacts with TAX1BP1; this CC interaction negatively regulates RIPK1 ubiquitination CC (PubMed:17703191). {ECO:0000250|UniProtKB:Q60855, CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10358032, CC ECO:0000269|PubMed:10409763, ECO:0000269|PubMed:11116146, CC ECO:0000269|PubMed:11734559, ECO:0000269|PubMed:11854271, CC ECO:0000269|PubMed:14754897, ECO:0000269|PubMed:16127453, CC ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:17449468, CC ECO:0000269|PubMed:17703191, ECO:0000269|PubMed:18450452, CC ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:21887730, CC ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:22265414, CC ECO:0000269|PubMed:24130170, ECO:0000269|PubMed:25736436, CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:29681455, CC ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:8612133, CC ECO:0000269|PubMed:9044836, ECO:0000269|PubMed:9927690, CC ECO:0000269|Ref.35}. CC -!- SUBUNIT: (Microbial infection) Interacts with mumps virus protein SH; CC this interaction inhibits downstream NF-kappa-B pathway activation. CC {ECO:0000269|PubMed:28659487}. CC -!- SUBUNIT: (Microbial infection) Interacts with Murid herpesvirus 1 CC protein RIR1. {ECO:0000269|PubMed:18442983}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP CC homotypic interaction motif); this interaction prevents necroptosis CC activation. {ECO:0000269|PubMed:25674983}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP CC homotypic interaction motif); this interaction prevents necroptosis CC activation. {ECO:0000269|PubMed:25674983}. CC -!- INTERACTION: CC Q13546; P04083: ANXA1; NbExp=5; IntAct=EBI-358507, EBI-354007; CC Q13546; Q13490: BIRC2; NbExp=5; IntAct=EBI-358507, EBI-514538; CC Q13546; Q13489: BIRC3; NbExp=3; IntAct=EBI-358507, EBI-517709; CC Q13546; Q92851: CASP10; NbExp=2; IntAct=EBI-358507, EBI-495095; CC Q13546; Q14790: CASP8; NbExp=28; IntAct=EBI-358507, EBI-78060; CC Q13546; Q8IVM0: CCDC50; NbExp=2; IntAct=EBI-358507, EBI-723996; CC Q13546; P48729: CSNK1A1; NbExp=5; IntAct=EBI-358507, EBI-1383726; CC Q13546; Q13158: FADD; NbExp=11; IntAct=EBI-358507, EBI-494804; CC Q13546; Q9Y6K9: IKBKG; NbExp=8; IntAct=EBI-358507, EBI-81279; CC Q13546; Q9ULZ3: PYCARD; NbExp=2; IntAct=EBI-358507, EBI-751215; CC Q13546; Q13546: RIPK1; NbExp=10; IntAct=EBI-358507, EBI-358507; CC Q13546; Q9Y572: RIPK3; NbExp=26; IntAct=EBI-358507, EBI-298250; CC Q13546; P19438: TNFRSF1A; NbExp=6; IntAct=EBI-358507, EBI-299451; CC Q13546; Q13077: TRAF1; NbExp=6; IntAct=EBI-358507, EBI-359224; CC Q13546; Q12933: TRAF2; NbExp=8; IntAct=EBI-358507, EBI-355744; CC Q13546; Q13114: TRAF3; NbExp=3; IntAct=EBI-358507, EBI-357631; CC Q13546; Q13107: USP4; NbExp=4; IntAct=EBI-358507, EBI-723290; CC Q13546; B7UI21: nleB1; Xeno; NbExp=4; IntAct=EBI-358507, EBI-16070376; CC Q13546; PRO_0000449629 [P0DTD1]: rep; Xeno; NbExp=6; IntAct=EBI-358507, EBI-25475885; CC Q13546; U5TQE9: UL39; Xeno; NbExp=3; IntAct=EBI-358507, EBI-11894787; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q60855}. Cell CC membrane {ECO:0000250|UniProtKB:Q9ZUF4}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13546-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13546-2; Sequence=VSP_037690; CC -!- DOMAIN: The RIP homotypic interaction motif (RHIM) mediates interaction CC with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid CC serpentine fold, stabilized by hydrophobic packing and featuring an CC unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from CC RIPK3). {ECO:0000269|PubMed:29681455}. CC -!- DOMAIN: The death domain mediates dimerization and activation of its CC kinase activity during necroptosis and apoptosis (PubMed:29440439). It CC engages other DD-containing proteins as well as a central CC (intermediate) region important for NF-kB activation and RHIM-dependent CC signaling (PubMed:10356400). {ECO:0000269|PubMed:10356400, CC ECO:0000269|PubMed:29440439}. CC -!- PTM: (Microbial infection) Proteolytically cleaved by S.flexneri OspD3 CC within the RIP homotypic interaction motif (RHIM), leading to its CC degradation and inhibition of necroptosis. CC {ECO:0000269|PubMed:32657447}. CC -!- PTM: Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396, CC PubMed:31827281, PubMed:31827280). Cleavage is crucial for limiting CC TNF-induced apoptosis, necroptosis and inflammatory response CC (PubMed:31827281, PubMed:31827280). Cleavage abolishes NF-kappa-B CC activation and enhances the interaction of TRADD with FADD CC (PubMed:10521396). Proteolytically cleaved by CASP6 during intrinsic CC apoptosis (PubMed:22858542). {ECO:0000250|UniProtKB:Q60855, CC ECO:0000269|PubMed:10521396, ECO:0000269|PubMed:31827280, CC ECO:0000269|PubMed:31827281}. CC -!- PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation CC (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of CC Ser-161 by RIPK3 is necessary for the formation of the necroptosis- CC inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses CC its kinase activity and consequently prevents TNF-mediated RIPK1- CC dependent cell death (PubMed:30988283). Phosphorylated at Ser-320 by CC MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains CC by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity). This phosphorylation CC positively regulates RIPK1 interaction with RIPK3 to promote CC necroptosis but negatively regulates RIPK1 kinase activity and its CC interaction with FADD to mediate apoptosis (By similarity). CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:18408713, CC ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:30988283, CC ECO:0000269|PubMed:31827280}. CC -!- PTM: Deubiquitinated by USP7; this modification is required for TNF- CC alpha-induced apoptosis. {ECO:0000269|PubMed:24144979}. CC -!- PTM: Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear- CC linked type ubiquitin (PubMed:15258597, PubMed:16603398, CC PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, CC Ref.35, PubMed:17703191). Polyubiquitination with 'Lys-63'-linked CC chains by TRAF2 induces association with the IKK complex CC (PubMed:15258597). Deubiquitination of 'Lys-63'-linked chains and CC polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to CC RIPK1 proteasomal degradation and consequently down-regulates TNF- CC alpha-induced NF-kappa-B signaling (PubMed:15258597). 'Lys-48'-linked CC polyubiquitination by RFFL or RNF34 also promotes proteasomal CC degradation and negatively regulates TNF-alpha-induced NF-kappa-B CC signaling (PubMed:18450452, Ref.35). Linear polyubiquitinated; the CC head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by CC the LUBAC complex and decreases protein kinase activity CC (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD CC promotes the kinase activity (By similarity). Polyubiquitinated with CC 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, CC leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated CC with 'Lys-63'-linked chains by PELI1 (PubMed:29883609). Ubiquitination CC at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 CC is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By CC similarity). This ubiquitination is required for NF-kB activation, CC suppresses RIPK1 kinase activity and plays a critical role in CC preventing cell death during embryonic development (By similarity). CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:15258597, CC ECO:0000269|PubMed:16603398, ECO:0000269|PubMed:18450452, CC ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21931591, CC ECO:0000269|PubMed:29883609, ECO:0000269|Ref.35}. CC -!- PTM: (Microbial infection) Glycosylated at Arg-603 by enteropathogenic CC E.coli protein NleB1: arginine GlcNAcylation prevents CC homotypic/heterotypic death domain interactions. CC {ECO:0000305|PubMed:23955153}. CC -!- DISEASE: Immunodeficiency 57 with autoinflammation (IMD57) CC [MIM:618108]: An autosomal recessive primary immunodeficiency CC characterized by lymphopenia and recurrent viral, bacterial, and fungal CC infections. Patients exhibit early-onset inflammatory bowel disease CC involving the upper and lower gastrointestinal tract, and develop CC progressive polyarthritis. {ECO:0000269|PubMed:30026316}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. RIPK1-deficient immune cells from IMD57 patients have impaired CC proinflammatory signaling leading to dysregulated cytokine secretion CC and are prone to necroptosis. {ECO:0000269|PubMed:30026316}. CC -!- DISEASE: Autoinflammation with episodic fever and lymphadenopathy CC (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder CC characterized by early onset of recurrent episodes of unexplained CC fever, lymphadenopathy, hepatosplenomegaly, and increased levels of CC inflammatory cytokines and chemokines in patient serum. CC {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG65471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; 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; AK314176; BAG36858.1; -; mRNA. DR EMBL; AK304701; BAG65471.1; ALT_INIT; mRNA. DR EMBL; AY682848; AAT74626.1; -; Genomic_DNA. DR EMBL; AL031963; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC126254; AAI26255.1; -; mRNA. DR EMBL; BC126256; AAI26257.1; -; mRNA. DR EMBL; AB208926; BAD92163.1; -; mRNA. DR EMBL; U25994; AAC50137.1; -; mRNA. DR CCDS; CCDS4482.1; -. [Q13546-1] DR CCDS; CCDS93851.1; -. [Q13546-2] DR PIR; T09479; T09479. DR RefSeq; NP_003795.2; NM_003804.4. [Q13546-1] DR RefSeq; XP_005249514.2; XM_005249457.3. DR PDB; 4ITH; X-ray; 2.25 A; A/B=1-294. DR PDB; 4ITI; X-ray; 2.86 A; A/B=1-294. DR PDB; 4ITJ; X-ray; 1.80 A; A/B=1-294. DR PDB; 4NEU; X-ray; 2.57 A; A/B=1-324. DR PDB; 5HX6; X-ray; 2.23 A; A/B=1-294. DR PDB; 5TX5; X-ray; 2.56 A; A/B=1-294. DR PDB; 5V7Z; NMR; -; B/D/F/H=532-549. DR PDB; 6AC5; X-ray; 1.45 A; A=561-671. DR PDB; 6C3E; X-ray; 2.60 A; A/B=2-294. DR PDB; 6C4D; X-ray; 2.52 A; A/B/C/D=2-294. DR PDB; 6HHO; X-ray; 3.49 A; A/B=1-294. DR PDB; 6NW2; X-ray; 2.00 A; A/B=1-294. DR PDB; 6NYH; X-ray; 2.10 A; A/B=1-294. DR PDB; 6OCQ; X-ray; 2.79 A; A/B=1-294. DR PDB; 6R5F; X-ray; 3.25 A; A/B/C/D=1-294. DR PDB; 6RLN; X-ray; 2.87 A; A/B=1-294. DR PDB; 7CJB; X-ray; 2.80 A; D/H/L/P=189-203. DR PDB; 7FCZ; X-ray; 2.21 A; A/B=1-294. DR PDB; 7FD0; X-ray; 2.00 A; A/B=1-294. DR PDB; 7XMK; X-ray; 2.38 A; A/B=1-294. DR PDB; 7YDX; X-ray; 2.64 A; A/B=1-294. DR PDBsum; 4ITH; -. DR PDBsum; 4ITI; -. DR PDBsum; 4ITJ; -. DR PDBsum; 4NEU; -. DR PDBsum; 5HX6; -. DR PDBsum; 5TX5; -. DR PDBsum; 5V7Z; -. DR PDBsum; 6AC5; -. DR PDBsum; 6C3E; -. DR PDBsum; 6C4D; -. DR PDBsum; 6HHO; -. DR PDBsum; 6NW2; -. DR PDBsum; 6NYH; -. DR PDBsum; 6OCQ; -. DR PDBsum; 6R5F; -. DR PDBsum; 6RLN; -. DR PDBsum; 7CJB; -. DR PDBsum; 7FCZ; -. DR PDBsum; 7FD0; -. DR PDBsum; 7XMK; -. DR PDBsum; 7YDX; -. DR AlphaFoldDB; Q13546; -. DR BMRB; Q13546; -. DR SMR; Q13546; -. DR BioGRID; 114274; 197. DR ComplexPortal; CPX-1907; Ripoptosome. DR CORUM; Q13546; -. DR DIP; DIP-433N; -. DR IntAct; Q13546; 94. DR MINT; Q13546; -. DR STRING; 9606.ENSP00000259808; -. DR BindingDB; Q13546; -. DR ChEMBL; CHEMBL5464; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q13546; -. DR GuidetoPHARMACOLOGY; 2189; -. DR GlyCosmos; Q13546; 3 sites, 1 glycan. DR GlyGen; Q13546; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; Q13546; -. DR MetOSite; Q13546; -. DR PhosphoSitePlus; Q13546; -. DR BioMuta; RIPK1; -. DR DMDM; 60393639; -. DR CPTAC; CPTAC-1053; -. DR CPTAC; CPTAC-900; -. DR CPTAC; CPTAC-901; -. DR CPTAC; CPTAC-902; -. DR EPD; Q13546; -. DR jPOST; Q13546; -. DR MassIVE; Q13546; -. DR MaxQB; Q13546; -. DR PaxDb; 9606-ENSP00000259808; -. DR PeptideAtlas; Q13546; -. DR ProteomicsDB; 59527; -. [Q13546-1] DR ProteomicsDB; 59528; -. [Q13546-2] DR Pumba; Q13546; -. DR Antibodypedia; 4145; 731 antibodies from 43 providers. DR DNASU; 8737; -. DR Ensembl; ENST00000259808.9; ENSP00000259808.3; ENSG00000137275.16. [Q13546-1] DR Ensembl; ENST00000380409.3; ENSP00000369773.3; ENSG00000137275.16. [Q13546-2] DR GeneID; 8737; -. DR KEGG; hsa:8737; -. DR MANE-Select; ENST00000259808.9; ENSP00000259808.3; NM_001354930.2; NP_001341859.1. DR UCSC; uc003mux.4; human. [Q13546-1] DR AGR; HGNC:10019; -. DR CTD; 8737; -. DR DisGeNET; 8737; -. DR GeneCards; RIPK1; -. DR HGNC; HGNC:10019; RIPK1. DR HPA; ENSG00000137275; Low tissue specificity. DR MalaCards; RIPK1; -. DR MIM; 603453; gene. DR MIM; 618108; phenotype. DR MIM; 618852; phenotype. DR neXtProt; NX_Q13546; -. DR OpenTargets; ENSG00000137275; -. DR Orphanet; 529977; Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome. DR PharmGKB; PA34394; -. DR VEuPathDB; HostDB:ENSG00000137275; -. DR eggNOG; KOG0192; Eukaryota. DR GeneTree; ENSGT00940000159347; -. DR HOGENOM; CLU_017229_0_0_1; -. DR InParanoid; Q13546; -. DR OrthoDB; 3997405at2759; -. DR PhylomeDB; Q13546; -. DR TreeFam; TF106506; -. DR BRENDA; 2.7.10.2; 2681. DR PathwayCommons; Q13546; -. DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand. DR Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment. DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1. DR Reactome; R-HSA-2562578; TRIF-mediated programmed cell death. DR Reactome; R-HSA-3295583; TRP channels. DR Reactome; R-HSA-3371378; Regulation by c-FLIP. DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-5218900; CASP8 activity is inhibited. DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. DR Reactome; R-HSA-5357956; TNFR1-induced NF-kappa-B signaling pathway. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-69416; Dimerization of procaspase-8. DR Reactome; R-HSA-75893; TNF signaling. DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death. DR Reactome; R-HSA-933543; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10. DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-9692913; SARS-CoV-1-mediated effects on programmed cell death. DR Reactome; R-HSA-9693928; Defective RIPK1-mediated regulated necrosis. DR SignaLink; Q13546; -. DR SIGNOR; Q13546; -. DR BioGRID-ORCS; 8737; 38 hits in 1199 CRISPR screens. DR ChiTaRS; RIPK1; human. DR GeneWiki; RIPK1; -. DR GenomeRNAi; 8737; -. DR Pharos; Q13546; Tchem. DR PRO; PR:Q13546; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q13546; Protein. DR Bgee; ENSG00000137275; Expressed in granulocyte and 154 other cell types or tissues. DR ExpressionAtlas; Q13546; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0031264; C:death-inducing signaling complex; IDA:BHF-UCL. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0043235; C:receptor complex; IDA:BHF-UCL. DR GO; GO:0097342; C:ripoptosome; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0070513; F:death domain binding; IPI:BHF-UCL. DR GO; GO:0005123; F:death receptor binding; IPI:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IBA:GO_Central. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; IEA:Ensembl. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:1990000; P:amyloid fibril formation; IMP:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:ARUK-UCL. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0035556; P:intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB. DR GO; GO:0097527; P:necroptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl. DR GO; GO:0060546; P:negative regulation of necroptotic process; ISS:UniProtKB. DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB. DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IEA:Ensembl. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ARUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB. DR GO; GO:0070105; P:positive regulation of interleukin-6-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB. DR GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB. DR GO; GO:1903800; P:positive regulation of miRNA processing; IDA:ARUK-UCL. DR GO; GO:0060545; P:positive regulation of necroptotic process; IMP:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:0043068; P:positive regulation of programmed cell death; IMP:UniProtKB. DR GO; GO:0062100; P:positive regulation of programmed necrotic cell death; IMP:BHF-UCL. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; TAS:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL. DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0097300; P:programmed necrotic cell death; ISS:ARUK-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL. DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB. DR GO; GO:0070926; P:regulation of ATP:ADP antiporter activity; IMP:BHF-UCL. DR GO; GO:0006979; P:response to oxidative stress; IMP:BHF-UCL. DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:BHF-UCL. DR GO; GO:0097343; P:ripoptosome assembly; IMP:UniProtKB. DR GO; GO:1901026; P:ripoptosome assembly involved in necroptotic process; IEA:Ensembl. DR GO; GO:0070231; P:T cell apoptotic process; ISS:UniProtKB. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IC:BHF-UCL. DR CDD; cd08777; Death_RIP1; 1. DR CDD; cd14027; STKc_RIP1; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR000488; Death_domain. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR037934; RIP1_Death. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR23257:SF983; RECEPTOR INTERACTING SERINE_THREONINE KINASE 1; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00005; DEATH; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50017; DEATH_DOMAIN; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q13546; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; ATP-binding; Cell membrane; KW Cytoplasm; Disease variant; Glycoprotein; Host-virus interaction; KW Inflammatory response; Isopeptide bond; Kinase; Membrane; Necrosis; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Ubl conjugation. FT CHAIN 1..671 FT /note="Receptor-interacting serine/threonine-protein kinase FT 1" FT /id="PRO_0000086606" FT DOMAIN 17..289 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 583..669 FT /note="Death" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064" FT REGION 290..582 FT /note="Interaction with SQSTM1" FT /evidence="ECO:0000269|PubMed:10356400" FT REGION 331..354 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 389..458 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 531..547 FT /note="RIP homotypic interaction motif (RHIM)" FT /evidence="ECO:0000269|PubMed:11734559, FT ECO:0000269|PubMed:29681455" FT COMPBIAS 331..346 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 403..420 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 423..458 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 138 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 23..31 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 45 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT SITE 324..325 FT /note="Cleavage; by CASP8" FT /evidence="ECO:0000269|PubMed:10521396, FT ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281" FT MOD_RES 6 FT /note="Phosphoserine; by IKKA and IKKB" FT /evidence="ECO:0000269|PubMed:18408713" FT MOD_RES 20 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000255" FT MOD_RES 25 FT /note="Phosphoserine; by IKKA and IKKB" FT /evidence="ECO:0000269|PubMed:18408713, FT ECO:0000269|PubMed:30988283" FT MOD_RES 161 FT /note="Phosphoserine; by RIPK3 and autocatalysis" FT /evidence="ECO:0000255" FT MOD_RES 166 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000255, ECO:0000269|PubMed:29440439, FT ECO:0000269|PubMed:31827280" FT MOD_RES 303 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:18408713" FT MOD_RES 320 FT /note="Phosphoserine; by MAP3K7" FT /evidence="ECO:0000269|PubMed:18408713, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 331 FT /note="Phosphoserine; by MAP3K7" FT /evidence="ECO:0000250|UniProtKB:Q60855" FT MOD_RES 333 FT /note="Phosphoserine; by MAP3K7" FT /evidence="ECO:0000269|PubMed:18408713" FT MOD_RES 384 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15144186" FT CARBOHYD 603 FT /note="(Microbial infection) N-beta-linked (GlcNAc) FT arginine" FT /evidence="ECO:0000269|PubMed:30979585, FT ECO:0000305|PubMed:23955153, ECO:0007744|PDB:6AC5" FT CROSSLNK 377 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:16603398" FT VAR_SEQ 108..153 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_037690" FT VARIANT 64 FT /note="A -> V (in a colorectal adenocarcinoma sample; FT somatic mutation; dbSNP:rs774996232)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041039" FT VARIANT 81 FT /note="V -> I (in a colorectal adenocarcinoma sample; FT somatic mutation; dbSNP:rs758268804)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041040" FT VARIANT 220 FT /note="A -> V (in a colorectal adenocarcinoma sample; FT somatic mutation; dbSNP:rs759012409)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041041" FT VARIANT 234 FT /note="E -> K (in dbSNP:rs17548383)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_021109" FT VARIANT 324 FT /note="D -> H (in AIEFL; prevents cleavage by CASP8; FT increased kinase activity; increased inflammatory FT response)" FT /evidence="ECO:0000269|PubMed:31827280, FT ECO:0000269|PubMed:31827281" FT /id="VAR_083518" FT VARIANT 324 FT /note="D -> N (in AIEFL; prevents cleavage by CASP8; FT changed inflammatory response; dbSNP:rs1760720617)" FT /evidence="ECO:0000269|PubMed:31827281" FT /id="VAR_083519" FT VARIANT 324 FT /note="D -> V (in AIEFL; prevents cleavage by CASP8; FT increased kinase activity; increased inflammatory response; FT dbSNP:rs1760720924)" FT /evidence="ECO:0000269|PubMed:31827280" FT /id="VAR_084135" FT VARIANT 324 FT /note="D -> Y (in AIEFL; prevents cleavage by CASP8; FT changed inflammatory response)" FT /evidence="ECO:0000269|PubMed:31827281" FT /id="VAR_083520" FT VARIANT 404 FT /note="A -> S (in dbSNP:rs34872409)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041042" FT VARIANT 438 FT /note="A -> V (in dbSNP:rs3173519)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:7538908, ECO:0000269|PubMed:8612133" FT /id="VAR_058285" FT VARIANT 443 FT /note="A -> V (in dbSNP:rs35722193)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041043" FT VARIANT 569 FT /note="A -> V (in dbSNP:rs55861377)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041044" FT MUTAGEN 25 FT /note="S->D: Phophomimetic mutant. Significant loss of FT kinase activity." FT /evidence="ECO:0000269|PubMed:30988283" FT MUTAGEN 45 FT /note="K->A: Abolishes kinase activity." FT /evidence="ECO:0000269|PubMed:30988283, FT ECO:0000269|PubMed:8612133" FT MUTAGEN 161 FT /note="S->A: Decreases RIPK1 kinase activity." FT /evidence="ECO:0000269|PubMed:18408713" FT MUTAGEN 161 FT /note="S->E: No effect on RIPK1 autophosphorylation." FT /evidence="ECO:0000269|PubMed:18408713" FT MUTAGEN 324 FT /note="D->K: Abolishes cleavage by caspase-8." FT /evidence="ECO:0000269|PubMed:10521396" FT MUTAGEN 377 FT /note="K->R: Abolishes RIP-mediated NF-Kappa-B activation." FT /evidence="ECO:0000269|PubMed:16603398" FT MUTAGEN 536 FT /note="S->C: Strongly reduced homodimerization and FT interaction with RIPK3." FT /evidence="ECO:0000269|PubMed:29681455" FT MUTAGEN 539..542 FT /note="IQIG->AAAA: Abolished cleavage by S.flexneri OspD3." FT /evidence="ECO:0000269|PubMed:32657447" FT MUTAGEN 599 FT /note="K->R: Blocks homodimerization, necroptosis and FT apoptosis." FT /evidence="ECO:0000269|PubMed:29440439" FT MUTAGEN 603 FT /note="R->A: Abolished GlcNAcylation by E.coli NleB1." FT /evidence="ECO:0000269|PubMed:30979585" FT CONFLICT 258 FT /note="R -> I (in Ref. 3; BAG36858)" FT /evidence="ECO:0000305" FT CONFLICT 286 FT /note="R -> S (in Ref. 3; BAG36858)" FT /evidence="ECO:0000305" FT CONFLICT 514 FT /note="T -> S (in Ref. 8; AAC50137)" FT /evidence="ECO:0000305" FT STRAND 10..12 FT /evidence="ECO:0007829|PDB:7FD0" FT HELIX 14..16 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 17..19 FT /evidence="ECO:0007829|PDB:5HX6" FT STRAND 20..22 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 26..28 FT /evidence="ECO:0007829|PDB:7FD0" FT STRAND 30..36 FT /evidence="ECO:0007829|PDB:4ITJ" FT TURN 37..39 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 40..51 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 54..56 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 57..68 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 78..84 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 87..93 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 100..104 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 106..108 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 112..131 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 141..143 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 152..154 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 163..168 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 171..173 FT /evidence="ECO:0007829|PDB:4ITH" FT HELIX 190..192 FT /evidence="ECO:0007829|PDB:6NW2" FT HELIX 195..197 FT /evidence="ECO:0007829|PDB:4ITJ" FT STRAND 201..203 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 207..223 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 228..230 FT /evidence="ECO:0007829|PDB:6C4D" FT HELIX 234..242 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 249..251 FT /evidence="ECO:0007829|PDB:4ITJ" FT TURN 252..255 FT /evidence="ECO:0007829|PDB:6C3E" FT HELIX 258..267 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 272..274 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 278..292 FT /evidence="ECO:0007829|PDB:4ITJ" FT HELIX 294..296 FT /evidence="ECO:0007829|PDB:4NEU" FT HELIX 297..309 FT /evidence="ECO:0007829|PDB:4NEU" FT TURN 310..312 FT /evidence="ECO:0007829|PDB:4NEU" FT STRAND 533..542 FT /evidence="ECO:0007829|PDB:5V7Z" FT HELIX 575..577 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 584..593 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 599..604 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 609..618 FT /evidence="ECO:0007829|PDB:6AC5" FT TURN 619..622 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 624..643 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 646..655 FT /evidence="ECO:0007829|PDB:6AC5" FT HELIX 659..668 FT /evidence="ECO:0007829|PDB:6AC5" 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 //