RIPK1_MOUSE
ID RIPK1_MOUSE Reviewed; 656 AA.
AC Q60855; Q3U0J3; Q8CD90;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 207.
DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 1 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887, ECO:0000269|PubMed:31827280};
DE AltName: Full=Cell death protein RIP {ECO:0000303|PubMed:7538908};
DE AltName: Full=Receptor-interacting protein 1 {ECO:0000303|PubMed:17301840};
DE Short=RIP-1 {ECO:0000303|PubMed:17301840};
GN Name=Ripk1 {ECO:0000312|MGI:MGI:108212};
GN Synonyms=Rinp, Rip {ECO:0000303|PubMed:7538908};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC STRAIN=C57BL/6 X CBA; TISSUE=Thymus;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Spleen, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, and Liver;
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 [4]
RP FUNCTION.
RX PubMed=12654725; DOI=10.1101/gad.1062403;
RA Hur G.M., Lewis J., Yang Q., Lin Y., Nakano H., Nedospasov S., Liu Z.G.;
RT "The death domain kinase RIP has an essential role in DNA damage-induced
RT NF-kappa B activation.";
RL Genes Dev. 17:873-882(2003).
RN [5]
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 [6]
RP INTERACTION WITH MURID HERPESVIRUS 1 RIR1 (MICROBIAL INFECTION).
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 [7]
RP FUNCTION, AND INTERACTION WITH ZBP1.
RX PubMed=19590578; DOI=10.1038/embor.2009.109;
RA Rebsamen M., Heinz L.X., Meylan E., Michallet M.C., Schroder K.,
RA Hofmann K., Vazquez J., Benedict C.A., Tschopp J.;
RT "DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs
RT to activate NF-kappaB.";
RL EMBO Rep. 10:916-922(2009).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-313 AND SER-321, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Lung, Pancreas, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [9]
RP INTERACTION WITH ZBP1, AND SUBCELLULAR LOCATION.
RX PubMed=23283962; DOI=10.1128/jvi.02860-12;
RA Pham T.H., Kwon K.M., Kim Y.E., Kim K.K., Ahn J.H.;
RT "DNA sensing-independent inhibition of herpes simplex virus 1 replication
RT by DAI/ZBP1.";
RL J. Virol. 87:3076-3086(2013).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813849; DOI=10.1016/j.cell.2014.04.019;
RA Rickard J.A., O'Donnell J.A., Evans J.M., Lalaoui N., Poh A.R., Rogers T.,
RA Vince J.E., Lawlor K.E., Ninnis R.L., Anderton H., Hall C., Spall S.K.,
RA Phesse T.J., Abud H.E., Cengia L.H., Corbin J., Mifsud S., Di Rago L.,
RA Metcalf D., Ernst M., Dewson G., Roberts A.W., Alexander W.S., Murphy J.M.,
RA Ekert P.G., Masters S.L., Vaux D.L., Croker B.A., Gerlic M., Silke J.;
RT "RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency
RT hematopoiesis.";
RL Cell 157:1175-1188(2014).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813850; DOI=10.1016/j.cell.2014.04.018;
RA Dillon C.P., Weinlich R., Rodriguez D.A., Cripps J.G., Quarato G.,
RA Gurung P., Verbist K.C., Brewer T.L., Llambi F., Gong Y.N., Janke L.J.,
RA Kelliher M.A., Kanneganti T.D., Green D.R.;
RT "RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.";
RL Cell 157:1189-1202(2014).
RN [12]
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 [13]
RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF ASP-138.
RX PubMed=24557836; DOI=10.1126/science.1249361;
RA Newton K., Dugger D.L., Wickliffe K.E., Kapoor N., de Almagro M.C.,
RA Vucic D., Komuves L., Ferrando R.E., French D.M., Webster J.,
RA Roose-Girma M., Warming S., Dixit V.M.;
RT "Activity of protein kinase RIPK3 determines whether cells die by
RT necroptosis or apoptosis.";
RL Science 343:1357-1360(2014).
RN [14]
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF 529-GLN--GLY-531.
RX PubMed=27819681; DOI=10.1038/nature20558;
RA Lin J., Kumari S., Kim C., Van T.M., Wachsmuth L., Polykratis A.,
RA Pasparakis M.;
RT "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.";
RL Nature 540:124-128(2016).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, PHOSPHORYLATION AT
RP SER-166, AND MUTAGENESIS OF 529-GLN--GLY-531.
RX PubMed=27819682; DOI=10.1038/nature20559;
RA Newton K., Wickliffe K.E., Maltzman A., Dugger D.L., Strasser A.,
RA Pham V.C., Lill J.R., Roose-Girma M., Warming S., Solon M., Ngu H.,
RA Webster J.D., Dixit V.M.;
RT "RIPK1 inhibits ZBP1-driven necroptosis during development.";
RL Nature 540:129-133(2016).
RN [16]
RP FUNCTION, PHOSPHORYLATION AT SER-321; SER-332 AND SER-334, MUTAGENESIS OF
RP SER-321; SER-332; SER-334 AND SER-336, UBIQUITINATION BY BIRC2/C-IAP1 AND
RP BIRC3/C-IAP2, AND INTERACTION WITH FADD AND RIPK3.
RX PubMed=28842570; DOI=10.1038/s41467-017-00406-w;
RA Geng J., Ito Y., Shi L., Amin P., Chu J., Ouchida A.T., Mookhtiar A.K.,
RA Zhao H., Xu D., Shan B., Najafov A., Gao G., Akira S., Yuan J.;
RT "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates
RT apoptosis and necroptosis.";
RL Nat. Commun. 8:359-359(2017).
RN [17]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, UBIQUITINATION, DEUBIQUITINATION,
RP AND PHOSPHORYLATION AT SER-166.
RX PubMed=28701375; DOI=10.1101/gad.299776.117;
RA Wei R., Xu L.W., Liu J., Li Y., Zhang P., Shan B., Lu X., Qian L., Wu Z.,
RA Dong K., Zhu H., Pan L., Yuan J., Pan H.;
RT "SPATA2 regulates the activation of RIPK1 by modulating linear
RT ubiquitination.";
RL Genes Dev. 31:1162-1176(2017).
RN [18]
RP INTERACTION WITH 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 [19]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, MUTAGENESIS OF LYS-45; ASP-138 AND
RP LYS-584, INTERACTION WITH FADD, IDENTIFICATION IN COMPLEX IIA, DOMAIN
RP DEATH, 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 [20]
RP FUNCTION, PROTEOLYTIC PROCESSING, SITE, AND MUTAGENESIS OF ASP-325.
RX PubMed=30867408; DOI=10.1038/s41419-019-1490-8;
RA Zhang X., Dowling J.P., Zhang J.;
RT "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic
RT development.";
RL Cell Death Dis. 10:245-245(2019).
RN [21]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30185824; DOI=10.1038/s41418-018-0166-8;
RA Anderton H., Bandala-Sanchez E., Simpson D.S., Rickard J.A., Ng A.P.,
RA Di Rago L., Hall C., Vince J.E., Silke J., Liccardi G., Feltham R.;
RT "RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during
RT development.";
RL Cell Death Differ. 26:877-889(2019).
RN [22]
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 [23]
RP FUNCTION.
RX PubMed=31358656; DOI=10.4049/jimmunol.1900216;
RA Ingram J.P., Thapa R.J., Fisher A., Tummers B., Zhang T., Yin C.,
RA Rodriguez D.A., Guo H., Lane R., Williams R., Slifker M.J.,
RA Basagoudanavar S.H., Rall G.F., Dillon C.P., Green D.R., Kaiser W.J.,
RA Balachandran S.;
RT "ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence
RT of RIPK1.";
RL J. Immunol. 203:1348-1355(2019).
RN [24]
RP INTERACTION WITH MURID HERPESVIRUS 1 RIR1 (MICROBIAL INFECTION).
RX PubMed=30498077; DOI=10.15252/embr.201846518;
RA Pham C.L., Shanmugam N., Strange M., O'Carroll A., Brown J.W., Sierecki E.,
RA Gambin Y., Steain M., Sunde M.;
RT "Viral M45 and necroptosis-associated proteins form heteromeric amyloid
RT assemblies.";
RL EMBO Rep. 20:0-0(2019).
RN [25]
RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-6; SER-25; SER-166 AND
RP THR-169, AND MUTAGENESIS OF SER-6; 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 [26]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH MAP3K7; CFLAR; CASP8; FADD
RP AND RIPK3, UBIQUITINATION AT LYS-376, MUTAGENESIS OF LYS-376, AND
RP PHOSPHORYLATION AT SER-166.
RX PubMed=31519887; DOI=10.1038/s41467-019-12033-8;
RA Tang Y., Tu H., Zhang J., Zhao X., Wang Y., Qin J., Lin X.;
RT "K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell
RT death during embryogenesis and inflammation.";
RL Nat. Commun. 10:4157-4157(2019).
RN [27]
RP FUNCTION, CATALYTIC ACTIVITY, UBIQUITINATION AT LYS-376, MUTAGENESIS OF
RP LYS-376, PHOSPHORYLATION AT SER-166, AND INTERACTION WITH NEMO.
RX PubMed=31519886; DOI=10.1038/s41467-019-11839-w;
RA Zhang X., Zhang H., Xu C., Li X., Li M., Wu X., Pu W., Zhou B., Wang H.,
RA Li D., Ding Q., Ying H., Wang H., Zhang H.;
RT "Ubiquitination of RIPK1 suppresses programmed cell death by regulating
RT RIPK1 kinase activation during embryogenesis.";
RL Nat. Commun. 10:4158-4158(2019).
RN [28]
RP FUNCTION, CATALYTIC ACTIVITY, PROTEOLYTIC PROCESSING, SITE, AND MUTAGENESIS
RP OF ASP-138 AND ASP-325.
RX PubMed=31511692; DOI=10.1016/j.immuni.2013.06.018;
RA Newton K., Wickliffe K.E., Dugger D.L., Maltzman A., Roose-Girma M.,
RA Dohse M., Komuves L., Webster J.D., Dixit V.M.;
RT "Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and
RT necroptosis.";
RL Nature 574:428-431(2019).
RN [29]
RP FUNCTION, CLEAVAGE BY CASP8, AND MUTAGENESIS OF ASP-138 AND ASP-325.
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 [30]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, CLEAVAGE BY CASP8, AND
RP MUTAGENESIS OF ASP-138 AND ASP-325.
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).
RN [31]
RP IDENTIFICATION IN THE AIM2 PANOPTOSOME COMPLEX.
RX PubMed=34471287; DOI=10.1038/s41586-021-03875-8;
RA Lee S., Karki R., Wang Y., Nguyen L.N., Kalathur R.C., Kanneganti T.D.;
RT "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host
RT defence.";
RL Nature 597:415-419(2021).
RN [32]
RP FUNCTION, AND INTERACTION WITH ZBP1.
RX PubMed=33397971; DOI=10.1038/s41467-020-20357-z;
RA Muendlein H.I., Connolly W.M., Magri Z., Smirnova I., Ilyukha V.,
RA Gautam A., Degterev A., Poltorak A.;
RT "ZBP1 promotes LPS-induced cell death and IL-1beta release via RHIM-
RT mediated interactions with RIPK1.";
RL Nat. Commun. 12:86-86(2021).
CC -!- FUNCTION: Serine-threonine kinase which is a key regulator of TNF-
CC mediated apoptosis, necroptosis and inflammatory pathways
CC (PubMed:24813849, PubMed:24813850, PubMed:24557836, PubMed:27819681,
CC PubMed:28842570, PubMed:31511692, PubMed:31827280, PubMed:31827281,
CC PubMed:33397971). Exhibits kinase activity-dependent functions that
CC regulate cell death and kinase-independent scaffold functions
CC regulating inflammatory signaling and cell survival (PubMed:24813849,
CC PubMed:24813850, PubMed:24557836, PubMed:28842570, PubMed:31519886,
CC PubMed:31519887). Has kinase-independent scaffold functions: upon
CC binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling
CC complex (TNF-RSC also known as complex I) where it acts as a scaffold
CC protein promoting cell survival, in part, by activating the canonical
CC NF-kappa-B pathway (PubMed:31519886, PubMed:31519887). Kinase activity
CC is essential to regulate necroptosis and apoptosis, two parallel forms
CC of cell death: upon activation of its protein kinase activity,
CC regulates assembly of two death-inducing complexes, namely complex IIa
CC (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-
CC RIPK3-MLKL), which drives necroptosis (PubMed:28842570,
CC PubMed:27819681, PubMed:27819682, PubMed:29440439, PubMed:30988283,
CC PubMed:31519886, PubMed:31519887). RIPK1 is required to limit CASP8-
CC dependent TNFR1-induced apoptosis (PubMed:24813849, PubMed:24813850,
CC PubMed:24557836). In normal conditions, RIPK1 acts as an inhibitor of
CC RIPK3-dependent necroptosis, a process mediated by RIPK3 component of
CC complex IIb, which catalyzes phosphorylation of MLKL upon induction by
CC ZBP1 (PubMed:24557836, PubMed:27819681, PubMed:27819682,
CC PubMed:31358656). Inhibits RIPK3-mediated necroptosis via FADD-mediated
CC recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced
CC necroptosis (PubMed:31358656). 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 (PubMed:30867408, PubMed:30185824). In addition to apoptosis and
CC necroptosis, also involved in inflammatory response by promoting
CC transcriptional production of pro-inflammatory cytokines, such as
CC interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates
CC RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-
CC phosphorylation (By similarity). Phosphorylates DAB2IP at 'Ser-728' in
CC a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK
CC apoptotic cascade (By similarity). Required for ZBP1-induced NF-kappa-B
CC activation in response to DNA damage (PubMed:12654725,
CC PubMed:19590578). {ECO:0000250|UniProtKB:Q13546,
CC ECO:0000269|PubMed:12654725, ECO:0000269|PubMed:19590578,
CC ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849,
CC ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:28842570,
CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30185824,
CC ECO:0000269|PubMed:30867408, ECO:0000269|PubMed:30988283,
CC ECO:0000269|PubMed:31358656, ECO:0000269|PubMed:31511692,
CC ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887,
CC ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281,
CC ECO:0000269|PubMed:33397971}.
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:27819682, ECO:0000269|PubMed:28701375,
CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30988283,
CC ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31519886,
CC ECO:0000269|PubMed:31519887, ECO:0000269|PubMed:31827280};
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:27819682,
CC ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:29440439,
CC ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31511692,
CC ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887,
CC ECO:0000269|PubMed:31827280};
CC -!- ACTIVITY REGULATION: Serine-threonine kinase activity is inhibited by
CC linear polyubiquitination ('Met-1'-linked) by the LUBAC complex.
CC {ECO:0000269|PubMed:28701375}.
CC -!- SUBUNIT: Homodimer (PubMed:29440439). Interacts (via RIP homotypic
CC interaction motif) with RIPK3 (via RIP homotypic interaction motif);
CC this interaction induces RIPK1 phosphorylation and formation of a
CC RIPK1-RIPK3 necroptosis-inducing complex (PubMed:31519887,
CC PubMed:28842570). 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 (By similarity). Interacts (via the death domain) with TNFRSF6
CC (via the death domain) and TRADD (via the death domain) (By
CC similarity). Is recruited by TRADD to TNFRSF1A in a TNF-dependent
CC process (By similarity). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and
CC TRAF3 (By similarity). Interacts with BNLF1 (By similarity). Interacts
CC with SQSTM1 upon TNF-alpha stimulation (By similarity). May interact
CC with MAVS/IPS1 (By similarity). Interacts with ZFAND5 (By similarity).
CC Interacts with RBCK1 (By similarity). Interacts with ZBP1
CC (PubMed:19590578, PubMed:23283962, PubMed:33397971). Interacts with
CC BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts (via kinase
CC domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a
CC TNF-alpha-dependent manner (By similarity). Interacts with ARHGEF2 (By
CC similarity). Interacts (via protein kinase domain) with RFFL; involved
CC in RIPK1 ubiquitination (By similarity). Interacts with RNF34; involved
CC in RIPK1 ubiquitination (By similarity). Interacts with TICAM1 and this
CC interaction is enhanced in the presence of WDFY1 (By similarity).
CC Interacts with PELI1 (PubMed:29883609). Interacts (via death domain)
CC with CRADD (via death domain); the interaction is direct (By
CC similarity). Component of complex IIa composed of at least RIPK1, FADD
CC and CASP8 (PubMed:29440439). Component of the AIM2 PANoptosome complex,
CC a multiprotein complex that drives inflammatory cell death (PANoptosis)
CC (PubMed:34471287). Interacts with MAP3K7, CFLAR and CASP8
CC (PubMed:31519887). Interacts with FADD (PubMed:29440439,
CC PubMed:31519887, PubMed:28842570). Interacts with NEMO
CC (PubMed:31519886). {ECO:0000250|UniProtKB:Q13546,
CC ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:23283962,
CC ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:29440439,
CC ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:31519887,
CC ECO:0000269|PubMed:33397971, ECO:0000269|PubMed:34471287}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Murid herpesvirus 1
CC protein RIR1. {ECO:0000269|PubMed:18442983,
CC ECO:0000269|PubMed:30498077}.
CC -!- INTERACTION:
CC Q60855; Q61160: Fadd; NbExp=8; IntAct=EBI-529119, EBI-524415;
CC Q60855; Q9QZL0: Ripk3; NbExp=4; IntAct=EBI-529119, EBI-2367423;
CC Q60855; P25118: Tnfrsf1a; NbExp=3; IntAct=EBI-529119, EBI-518014;
CC Q60855; Q3U0V2: Tradd; NbExp=2; IntAct=EBI-529119, EBI-1544032;
CC Q60855; P62991: Ubc; NbExp=5; IntAct=EBI-529119, EBI-413074;
CC Q60855; O43464: HTRA2; Xeno; NbExp=2; IntAct=EBI-529119, EBI-517086;
CC Q60855; P01375: TNF; Xeno; NbExp=3; IntAct=EBI-529119, EBI-359977;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23283962,
CC ECO:0000269|PubMed:7538908}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9ZUF4}.
CC -!- TISSUE SPECIFICITY: Found at low levels in all tissues.
CC {ECO:0000269|PubMed:7538908}.
CC -!- INDUCTION: In concanavalin A-treated splenocytes.
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 (By similarity). {ECO:0000250|UniProtKB:Q13546,
CC ECO:0000269|PubMed:29440439}.
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:0000250|UniProtKB:Q13546}.
CC -!- PTM: Proteolytically cleaved by CASP8 at Asp-325 (PubMed:30867408,
CC PubMed:31511692, PubMed:31827280). Cleavage is crucial for limiting
CC TNF-induced apoptosis, necroptosis and inflammatory response
CC (PubMed:30867408, PubMed:31511692, PubMed:31827281, PubMed:31827280).
CC Cleavage abolishes NF-kappa-B activation and enhances the interaction
CC of TRADD with FADD (By similarity). Proteolytically cleaved by CASP6
CC during intrinsic apoptosis (By similarity).
CC {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:30867408,
CC ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827280,
CC ECO:0000269|PubMed:31827281}.
CC -!- PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation
CC (By similarity). Phosphorylation of Ser-161 by RIPK3 is necessary for
CC the formation of the necroptosis-inducing complex (By similarity).
CC Phosphorylation at Ser-25 represses its kinase activity and
CC consequently prevents TNF-mediated RIPK1-dependent cell death
CC (PubMed:30988283). Phosphorylated at Ser-321 by MAP3K7 which requires
CC prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and
CC BIRC3/c-IAP2 (PubMed:28842570). This phosphorylation positively
CC regulates RIPK1 interaction with RIPK3 to promote necroptosis but
CC negatively regulates RIPK1 kinase activity and its interaction with
CC FADD to mediate apoptosis (PubMed:28842570).
CC {ECO:0000250|UniProtKB:Q13546, ECO:0000269|PubMed:28842570,
CC ECO:0000269|PubMed:30988283}.
CC -!- PTM: Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-
CC linked type ubiquitin (By similarity). Polyubiquitination with 'Lys-
CC 63'-linked chains by TRAF2 induces association with the IKK complex (By
CC similarity). 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 (By similarity). '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 (By similarity). Linear polyubiquitinated; the head-to-tail
CC linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC
CC complex and decreases protein kinase activity (PubMed:28701375).
CC Deubiquitination of linear polyubiquitin by CYLD promotes the kinase
CC activity (PubMed:28701375). Polyubiquitinated with 'Lys-48' by BIRC2/c-
CC IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (By
CC similarity). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (By
CC similarity). Ubiquitination at Lys-376 with 'Lys-63'-linked chains by
CC BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at
CC Ser-321 mediated by MAP3K7 (PubMed:28842570, PubMed:31519887,
CC PubMed:31519886). 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 (PubMed:31519887,
CC PubMed:31519886). {ECO:0000250|UniProtKB:Q13546,
CC ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:28842570,
CC ECO:0000269|PubMed:31519886, ECO:0000269|PubMed:31519887}.
CC -!- DISRUPTION PHENOTYPE: Mice exhibit severe multi-organ inflammation and
CC systemic cell death, which causes lethality of animals late in
CC gestation or shortly after birth (PubMed:24813849, PubMed:30185824).
CC Perinatal lethality observed in Ripk1 knockout mice is rescued in
CC knockout mice lacking both Ripk1 and Ripk3; mice however die the first
CC days of postnatal life (PubMed:24813849, PubMed:24813850,
CC PubMed:27819681, PubMed:27819682). Perinatal lethality observed in
CC Ripk1 knockout mice is rescued in knockout mice lacking both Ripk1 and
CC Casp8; mice however die the first days of postnatal life
CC (PubMed:24813849). Only mice lacking Ripk1, Ripk3 and Casp8 survive
CC past weaning and rescue lethality caused by the absence of Ripk1
CC (PubMed:24813849, PubMed:24813850). {ECO:0000269|PubMed:24813849,
CC ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:30185824}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
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; U25995; AAB60487.1; -; mRNA.
DR EMBL; AK030959; BAC27194.1; -; mRNA.
DR EMBL; AK156803; BAE33860.1; -; mRNA.
DR EMBL; BC050905; AAH50905.2; -; mRNA.
DR EMBL; BC054542; AAH54542.1; -; mRNA.
DR EMBL; BC058162; AAH58162.1; -; mRNA.
DR CCDS; CCDS26443.1; -.
DR PIR; I49299; I49299.
DR RefSeq; NP_033094.3; NM_009068.3.
DR RefSeq; XP_006516670.1; XM_006516607.3.
DR RefSeq; XP_006516672.1; XM_006516609.3.
DR AlphaFoldDB; Q60855; -.
DR SMR; Q60855; -.
DR BioGRID; 202896; 26.
DR ComplexPortal; CPX-1914; Ripoptosome.
DR DIP; DIP-34962N; -.
DR IntAct; Q60855; 25.
DR MINT; Q60855; -.
DR STRING; 10090.ENSMUSP00000129831; -.
DR BindingDB; Q60855; -.
DR ChEMBL; CHEMBL3784911; -.
DR iPTMnet; Q60855; -.
DR PhosphoSitePlus; Q60855; -.
DR EPD; Q60855; -.
DR jPOST; Q60855; -.
DR MaxQB; Q60855; -.
DR PaxDb; Q60855; -.
DR PeptideAtlas; Q60855; -.
DR PRIDE; Q60855; -.
DR ProteomicsDB; 254885; -.
DR Antibodypedia; 4145; 650 antibodies from 43 providers.
DR DNASU; 19766; -.
DR Ensembl; ENSMUST00000021844; ENSMUSP00000021844; ENSMUSG00000021408.
DR Ensembl; ENSMUST00000167374; ENSMUSP00000129831; ENSMUSG00000021408.
DR GeneID; 19766; -.
DR KEGG; mmu:19766; -.
DR UCSC; uc007qax.1; mouse.
DR CTD; 8737; -.
DR MGI; MGI:108212; Ripk1.
DR VEuPathDB; HostDB:ENSMUSG00000021408; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000159347; -.
DR HOGENOM; CLU_017229_0_0_1; -.
DR InParanoid; Q60855; -.
DR OMA; QIGSYNH; -.
DR OrthoDB; 346354at2759; -.
DR PhylomeDB; Q60855; -.
DR TreeFam; TF106506; -.
DR BRENDA; 2.7.10.2; 3474.
DR Reactome; R-MMU-140534; Caspase activation via Death Receptors in the presence of ligand.
DR Reactome; R-MMU-2562578; TRIF-mediated programmed cell death.
DR Reactome; R-MMU-3295583; TRP channels.
DR Reactome; R-MMU-3371378; Regulation by c-FLIP.
DR Reactome; R-MMU-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-MMU-5218900; CASP8 activity is inhibited.
DR Reactome; R-MMU-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-MMU-5675482; Regulation of necroptotic cell death.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-5689896; Ovarian tumor domain proteases.
DR Reactome; R-MMU-69416; Dimerization of procaspase-8.
DR Reactome; R-MMU-75893; TNF signaling.
DR Reactome; R-MMU-937041; IKK complex recruitment mediated by RIP1.
DR BioGRID-ORCS; 19766; 21 hits in 77 CRISPR screens.
DR ChiTaRS; Ripk1; mouse.
DR PRO; PR:Q60855; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q60855; protein.
DR Bgee; ENSMUSG00000021408; Expressed in renal corpuscle and 211 other tissues.
DR ExpressionAtlas; Q60855; baseline and differential.
DR Genevisible; Q60855; MM.
DR GO; GO:0031264; C:death-inducing signaling complex; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0043235; C:receptor complex; ISO:MGI.
DR GO; GO:0097342; C:ripoptosome; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0070513; F:death domain binding; ISO:MGI.
DR GO; GO:0005123; F:death receptor binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
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; IMP: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; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:1990000; P:amyloid fibril formation; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0008219; P:cell death; IMP:UniProtKB.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IMP:UniProtKB.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IMP:ARUK-UCL.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0070266; P:necroptotic process; IDA:UniProtKB.
DR GO; GO:0097527; P:necroptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IGI:MGI.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:UniProtKB.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IMP:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0010942; P:positive regulation of cell death; ISO:MGI.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IGI:MGI.
DR GO; GO:1905206; P:positive regulation of hydrogen peroxide-induced cell death; ISO:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:MGI.
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; ISO:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0045651; P:positive regulation of macrophage differentiation; ISO:MGI.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB.
DR GO; GO:1903800; P:positive regulation of miRNA maturation; ISO:MGI.
DR GO; GO:0060545; P:positive regulation of necroptotic process; ISO:MGI.
DR GO; GO:0010940; P:positive regulation of necrotic cell death; ISO:MGI.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IMP:UniProtKB.
DR GO; GO:0043068; P:positive regulation of programmed cell death; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:MGI.
DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:ARUK-UCL.
DR GO; GO:0097300; P:programmed necrotic cell death; IMP:ARUK-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IMP:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; ISS:UniProtKB.
DR GO; GO:0070926; P:regulation of ATP:ADP antiporter activity; ISO:MGI.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0034612; P:response to tumor necrosis factor; ISO:MGI.
DR GO; GO:0097343; P:ripoptosome assembly; ISS:UniProtKB.
DR GO; GO:1901026; P:ripoptosome assembly involved in necroptotic process; IGI:MGI.
DR GO; GO:0070231; P:T cell apoptotic process; IMP:UniProtKB.
DR CDD; cd08777; Death_RIP1; 1.
DR Gene3D; 1.10.533.10; -; 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; IPR025735; RHIM_dom.
DR InterPro; IPR037934; RIP1_Death.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF12721; RHIM; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 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; Cell membrane; Cytoplasm; 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..656
FT /note="Receptor-interacting serine/threonine-protein kinase
FT 1"
FT /id="PRO_0000086607"
FT DOMAIN 17..290
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 568..654
FT /note="Death"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT REGION 291..567
FT /note="Interaction with SQSTM1"
FT /evidence="ECO:0000250|UniProtKB:Q13546"
FT REGION 327..373
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 388..423
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 520..536
FT /note="RIP homotypic interaction motif (RHIM)"
FT /evidence="ECO:0000269|PubMed:18442983,
FT ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682"
FT COMPBIAS 328..368
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 401..423
FT /note="Basic and acidic 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 ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:31827280"
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 325..326
FT /note="Cleavage; by CASP8"
FT /evidence="ECO:0000269|PubMed:31511692,
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:30988283"
FT MOD_RES 25
FT /note="Phosphoserine; by IKKA and IKKB"
FT /evidence="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:0000269|PubMed:27819682,
FT ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:29440439,
FT ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31519886,
FT ECO:0000269|PubMed:31519887"
FT MOD_RES 169
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:30988283"
FT MOD_RES 304
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13546"
FT MOD_RES 313
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 321
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000269|PubMed:28842570,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 332
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000269|PubMed:28842570"
FT MOD_RES 334
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000269|PubMed:28842570"
FT MOD_RES 383
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13546"
FT CROSSLNK 376
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:31519886,
FT ECO:0000269|PubMed:31519887"
FT MUTAGEN 6
FT /note="S->A: Loss of phosphorylation. Does not protect
FT cells from TNF-induced cell death."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 6
FT /note="S->D: Phophomimetic mutant. Does not protect cells
FT from TNF-induced cell death."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 25
FT /note="S->A: Loss of phosphorylation. Does not protect
FT cells from TNF-induced cell death."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 25
FT /note="S->D: Phophomimetic mutant. Significant loss of
FT kinase activity. Protects cells from TNF-induced cell
FT death."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 45
FT /note="K->A: Loss of kinase activity. Protects cells from
FT TNF-induced cell death."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 45
FT /note="K->M: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:29440439"
FT MUTAGEN 138
FT /note="D->N: Abolished protein kinase activity and ability
FT to regulate apoptosis and necroptosis. Knockin mice are
FT viable."
FT /evidence="ECO:0000269|PubMed:24557836"
FT MUTAGEN 138
FT /note="D->N: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:29440439,
FT ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827280,
FT ECO:0000269|PubMed:31827281"
FT MUTAGEN 321
FT /note="S->A: Loss of phosphorylation. Promotes activation
FT of its kinase activity, proteolytic cleavage,
FT ubiquitination and interaction with FADD to mediate
FT apoptosis. Loss of phosphorylation at Ser-332 and Ser-334;
FT when associated with A-332; A-334 and A-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 321
FT /note="S->E: Inhibits its proteolytic cleavage and
FT interaction with FADD. Promotes its interaction with RIPK3
FT to mediate necroptosis; when associated with E-332; E-334
FT and E-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 325
FT /note="D->A: Loss of CASP8-mediated cleavage. Promotes both
FT FADD-dependent apoptosis and RIPK3-dependent necroptosis,
FT thus leading to embryonic lethality at midgestation stages
FT in knockin mice. Heterozygous knockin mice are viable and
FT grossly normal, but are hyperresponsive to inflammatory
FT stimuli."
FT /evidence="ECO:0000269|PubMed:30867408,
FT ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31827281"
FT MUTAGEN 325
FT /note="D->V,H: Loss of CASP8-mediated cleavage. Embryonic
FT lethality in knockin mice. Promotes activation of the
FT protein kinase activity, leading to increased cell death."
FT /evidence="ECO:0000269|PubMed:31827280"
FT MUTAGEN 332
FT /note="S->A: Loss of phosphorylation at Ser-332 and Ser-
FT 334; when associated with A-321; A-334 and A-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 332
FT /note="S->E: Promotes its interaction with RIPK3 to mediate
FT necroptosis; when associated with E-321; E-334 and E-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 334
FT /note="S->A: Loss of phosphorylation at Ser-332 and Ser-
FT 334; when associated with A-321; A-332 and A-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 334
FT /note="S->E: Promotes its interaction with RIPK3 to mediate
FT necroptosis; when associated with E-321; E-332 and E-336."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 336
FT /note="S->A: Loss of phosphorylation at Ser-332 and Ser-
FT 334; when associated with A-321; A-332 and A-334."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 336
FT /note="S->E: Promotes its interaction with RIPK3 to mediate
FT necroptosis; when associated with E-321; E-332 and E-334."
FT /evidence="ECO:0000269|PubMed:28842570"
FT MUTAGEN 376
FT /note="K->R: Loss of ubiquitination. Decreases TNF-alpha-
FT mediated NF-kappaB activation. Increases interaction with
FT CFLAR, CASP8, FADD AND RIPK3. Decreases interaction with
FT MAP3K7. Enhances kinase activity and promotes apoptosis and
FT necroptosis. Knockin mice display early embryonic lethality
FT resulting from excessive cell death and severe
FT inflammation."
FT /evidence="ECO:0000269|PubMed:31519886,
FT ECO:0000269|PubMed:31519887"
FT MUTAGEN 529..531
FT /note="QIG->AAA: In RIPK1(mRHIM); perinatal lethality in
FT knockin mice caused by Ripk3- and Zbp1-dependent
FT necroptosis. Lethality is prevented by Ripk3, Mlkl or Zbp1
FT deficiency. Knockin mice do not show defects caused by
FT Casp8-dependent apoptosis observed in knockout mice."
FT /evidence="ECO:0000269|PubMed:27819681,
FT ECO:0000269|PubMed:27819682"
FT MUTAGEN 584
FT /note="K->R: Blocks homodimerization, activation of its
FT kinase activity, formation of complex IIa, necroptosis and
FT apoptosis."
FT /evidence="ECO:0000269|PubMed:29440439"
FT CONFLICT 66
FT /note="M -> K (in Ref. 2; BAC27194)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 656 AA; 74854 MW; ABB350B523879933 CRC64;
MQPDMSLDNI KMASSDLLEK TDLDSGGFGK VSLCYHRSHG FVILKKVYTG PNRAEYNEVL
LEEGKMMHRL RHSRVVKLLG IIIEEGNYSL VMEYMEKGNL MHVLKTQIDV PLSLKGRIIV
EAIEGMCYLH DKGVIHKDLK PENILVDRDF HIKIADLGVA SFKTWSKLTK EKDNKQKEVS
STTKKNNGGT LYYMAPEHLN DINAKPTEKS DVYSFGIVLW AIFAKKEPYE NVICTEQFVI
CIKSGNRPNV EEILEYCPRE IISLMERCWQ AIPEDRPTFL GIEEEFRPFY LSHFEEYVEE
DVASLKKEYP DQSPVLQRMF SLQHDCVPLP PSRSNSEQPG SLHSSQGLQM GPVEESWFSS
SPEYPQDEND RSVQAKLQEE ASYHAFGIFA EKQTKPQPRQ NEAYNREEER KRRVSHDPFA
QQRARENIKS AGARGHSDPS TTSRGIAVQQ LSWPATQTVW NNGLYNQHGF GTTGTGVWYP
PNLSQMYSTY KTPVPETNIP GSTPTMPYFS GPVADDLIKY TIFNSSGIQI GNHNYMDVGL
NSQPPNNTCK EESTSRHQAI FDNTTSLTDE HLNPIRENLG RQWKNCARKL GFTESQIDEI
DHDYERDGLK EKVYQMLQKW LMREGTKGAT VGKLAQALHQ CCRIDLLNHL IRASQS
