RIPK2_HUMAN
ID RIPK2_HUMAN Reviewed; 540 AA.
AC O43353; B7Z748; Q6UWF0;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 2.
DT 03-AUG-2022, entry version 224.
DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=CARD-containing interleukin-1 beta-converting enzyme-associated kinase;
DE Short=CARD-containing IL-1 beta ICE-kinase;
DE AltName: Full=RIP-like-interacting CLARP kinase;
DE AltName: Full=Receptor-interacting protein 2;
DE Short=RIP-2;
DE AltName: Full=Tyrosine-protein kinase RIPK2;
DE EC=2.7.10.2;
GN Name=RIPK2; Synonyms=CARDIAK, RICK, RIP2; ORFNames=UNQ277/PRO314/PRO34092;
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), TISSUE SPECIFICITY, AND MUTAGENESIS
RP OF LYS-47.
RX PubMed=9575181; DOI=10.1074/jbc.273.20.12296;
RA Inohara N., del Peso L., Koseki T., Chen S., Nunez G.;
RT "RICK, a novel protein kinase containing a caspase recruitment domain,
RT interacts with CLARP and regulates CD95-mediated apoptosis.";
RL J. Biol. Chem. 273:12296-12300(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND MUTAGENESIS
RP OF LYS-47.
RC TISSUE=Endothelial cell;
RX PubMed=9642260; DOI=10.1074/jbc.273.27.16968;
RA McCarthy J.V., Ni J., Dixit V.M.;
RT "RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase.";
RL J. Biol. Chem. 273:16968-16975(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ACTIVE SITE, AND MUTAGENESIS OF
RP ASP-146.
RC TISSUE=Pancreatic adenocarcinoma;
RX PubMed=9705938; DOI=10.1016/s0960-9822(07)00352-1;
RA Thome M., Hofmann K., Burns K., Martinon F., Bodmer J.-L., Mattmann C.,
RA Tschopp J.;
RT "Identification of CARDIAK, a RIP-like kinase that associates with caspase-
RT 1.";
RL Curr. Biol. 8:885-888(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Synovium;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 [8]
RP FUNCTION.
RX PubMed=14638696; DOI=10.1074/jbc.c300460200;
RA Ruefli-Brasse A.A., Lee W.P., Hurst S., Dixit V.M.;
RT "Rip2 participates in Bcl10 signaling and T-cell receptor-mediated NF-
RT kappaB activation.";
RL J. Biol. Chem. 279:1570-1574(2004).
RN [9]
RP CATALYTIC ACTIVITY, AND PHOSPHORYLATION AT SER-176.
RX PubMed=16824733; DOI=10.1016/j.cellsig.2006.05.005;
RA Dorsch M., Wang A., Cheng H., Lu C., Bielecki A., Charron K., Clauser K.,
RA Ren H., Polakiewicz R.D., Parsons T., Li P., Ocain T., Xu Y.;
RT "Identification of a regulatory autophosphorylation site in the serine-
RT threonine kinase RIP2.";
RL Cell. Signal. 18:2223-2229(2006).
RN [10]
RP FUNCTION, INTERACTION WITH NOD1, AND MUTAGENESIS OF ARG-444; ARG-483 AND
RP ARG-488.
RX PubMed=17054981; DOI=10.1016/j.jmb.2006.09.067;
RA Manon F., Favier A., Nunez G., Simorre J.P., Cusack S.;
RT "Solution structure of NOD1 CARD and mutational analysis of its interaction
RT with the CARD of downstream kinase RICK.";
RL J. Mol. Biol. 365:160-174(2007).
RN [11]
RP INTERACTION WITH MAP3K4.
RX PubMed=18775659; DOI=10.1016/j.cub.2008.07.084;
RA Clark N.M., Marinis J.M., Cobb B.A., Abbott D.W.;
RT "MEKK4 sequesters RIP2 to dictate NOD2 signal specificity.";
RL Curr. Biol. 18:1402-1408(2008).
RN [12]
RP INTERACTION WITH IKBKG/NEMO AND MAP3K7/TAK1, FUNCTION, UBIQUITINATION AT
RP LYS-209, AND MUTAGENESIS OF LYS-209.
RX PubMed=18079694; DOI=10.1038/sj.emboj.7601962;
RA Hasegawa M., Fujimoto Y., Lucas P.C., Nakano H., Fukase K., Nunez G.,
RA Inohara N.;
RT "A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB
RT activation.";
RL EMBO J. 27:373-383(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-363; SER-527 AND SER-539, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531, 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 [15]
RP UBIQUITINATION BY ITCH, AND INTERACTION WITH NOD2.
RX PubMed=19592251; DOI=10.1016/j.cub.2009.06.038;
RA Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E.,
RA Abbott D.W.;
RT "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence
RT inflammatory signaling pathways.";
RL Curr. Biol. 19:1255-1263(2009).
RN [16]
RP UBIQUITINATION BY BIRC2 AND BIRC3.
RX PubMed=19464198; DOI=10.1016/j.immuni.2009.04.011;
RA Bertrand M.J., Doiron K., Labbe K., Korneluk R.G., Barker P.A., Saleh M.;
RT "Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate
RT immunity signaling by the pattern recognition receptors NOD1 and NOD2.";
RL Immunity 30:789-801(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-363; SER-393;
RP SER-527 AND SER-539, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [18]
RP FUNCTION, PHOSPHORYLATION AT TYR-474, AND MUTAGENESIS OF TYR-474.
RX PubMed=21123652; DOI=10.1101/gad.1964410;
RA Tigno-Aranjuez J.T., Asara J.M., Abbott D.W.;
RT "Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine
RT responses.";
RL Genes Dev. 24:2666-2677(2010).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-529, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
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 [21]
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 [22]
RP ACETYLATION AT THR-149; SER-174; SER-178; SER-178; SER-181; SER-183;
RP THR-189; SER-363; THR-397 AND SER-423 (MICROBIAL INFECTION).
RX PubMed=22520462; DOI=10.1016/j.chom.2012.02.009;
RA Meinzer U., Barreau F., Esmiol-Welterlin S., Jung C., Villard C., Leger T.,
RA Ben-Mkaddem S., Berrebi D., Dussaillant M., Alnabhani Z., Roy M.,
RA Bonacorsi S., Wolf-Watz H., Perroy J., Ollendorff V., Hugot J.P.;
RT "Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1
RT pathway and activates caspase-1 to induce intestinal barrier dysfunction.";
RL Cell Host Microbe 11:337-351(2012).
RN [23]
RP INTERACTION WITH NLRP10.
RX PubMed=22672233; DOI=10.1111/j.1462-5822.2012.01822.x;
RA Lautz K., Damm A., Menning M., Wenger J., Adam A.C., Zigrino P.,
RA Kremmer E., Kufer T.A.;
RT "NLRP10 enhances Shigella-induced pro-inflammatory responses.";
RL Cell. Microbiol. 14:1568-1583(2012).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN A COMPLEX WITH ARHGEF2
RP AND NOD2, INTERACTION WITH ARHGEF2 AND NOD2, PHOSPHORYLATION AT TYR-381,
RP AND MUTAGENESIS OF TYR-381.
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 [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-363; SER-527; SER-529 AND
RP SER-531, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [26]
RP UBIQUITINATION, AND DEUBIQUITINATION.
RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004;
RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M.,
RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D., Gyrd-Hansen M.;
RT "OTULIN restricts Met1-linked ubiquitination to control innate immune
RT signaling.";
RL Mol. Cell 50:818-830(2013).
RN [27]
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 [28]
RP INTERACTION WITH NOD2.
RX PubMed=27812135; DOI=10.1371/journal.pone.0165420;
RA Thiebaut R., Esmiol S., Lecine P., Mahfouz B., Hermant A., Nicoletti C.,
RA Parnis S., Perroy J., Borg J.P., Pascoe L., Hugot J.P., Ollendorff V.;
RT "Characterization and Genetic Analyses of New Genes Coding for NOD2
RT Interacting Proteins.";
RL PLoS ONE 11:E0165420-E0165420(2016).
RN [29]
RP INTERACTION WITH INAVA.
RX PubMed=28436939; DOI=10.1172/jci86282;
RA Yan J., Hedl M., Abraham C.;
RT "An inflammatory bowel disease-risk variant in INAVA decreases pattern
RT recognition receptor-induced outcomes.";
RL J. Clin. Invest. 127:2192-2205(2017).
RN [30]
RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION AT LYS-503, AND MUTAGENESIS
RP OF LYS-503.
RX PubMed=28656966; DOI=10.1038/ncomms15865;
RA Bist P., Cheong W.S., Ng A., Dikshit N., Kim B.H., Pulloor N.K.,
RA Khameneh H.J., Hedl M., Shenoy A.R., Balamuralidhar V., Malik N.B.A.,
RA Hong M., Neutzner A., Chin K.C., Kobayashi K.S., Bertoletti A.,
RA Mortellaro A., Abraham C., MacMicking J.D., Xavier R.J., Sukumaran B.;
RT "E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces
RT tolerance to MDP.";
RL Nat. Commun. 8:15865-15865(2017).
RN [31] {ECO:0007744|PDB:2N7Z, ECO:0007744|PDB:2N83}
RP STRUCTURE BY NMR OF 434-539 IN COMPLEX WITH NGFR, FUNCTION, AND MUTAGENESIS
RP OF GLN-437; ASP-467; LYS-471; ILE-496; GLU-500 AND ARG-528.
RX PubMed=26646181; DOI=10.7554/elife.11692;
RA Lin Z., Tann J.Y., Goh E.T., Kelly C., Lim K.B., Gao J.F., Ibanez C.F.;
RT "Structural basis of death domain signaling in the p75 neurotrophin
RT receptor.";
RL Elife 4:e11692-e11692(2015).
RN [32]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-259; VAL-268 AND ASN-313.
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).
CC -!- FUNCTION: Serine/threonine/tyrosine kinase that plays an essential role
CC in modulation of innate and adaptive immune responses (PubMed:9575181,
CC PubMed:9642260, PubMed:17054981, PubMed:21123652, PubMed:21887730,
CC PubMed:28656966). Upon stimulation by bacterial peptidoglycans, NOD1
CC and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD
CC domains (PubMed:17054981, PubMed:21123652, PubMed:28656966).
CC Contributes to the tyrosine phosphorylation of the guanine exchange
CC factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B
CC activation by NOD2 (PubMed:21123652). Once recruited, RIPK2
CC autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by
CC E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated
CC protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and
CC induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent
CC activation of IKBKB/IKKB (PubMed:18079694). In turn, NF-kappa-B is
CC released from NF-kappa-B inhibitors and translocates into the nucleus
CC where it activates the transcription of hundreds of genes involved in
CC immune response, growth control, or protection against apoptosis
CC (PubMed:18079694). Also plays a role during engagement of the T-cell
CC receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-
CC kappa-B activation (PubMed:14638696). Plays a role in the inactivation
CC of RHOA in response to NGFR signaling (PubMed:26646181).
CC {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981,
CC ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652,
CC ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:26646181,
CC ECO:0000269|PubMed:28656966, ECO:0000269|PubMed:9575181,
CC ECO:0000269|PubMed:9642260}.
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 -!- 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;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10027,
CC ECO:0000269|PubMed:16824733};
CC -!- SUBUNIT: Found in a signaling complex consisting of at least ARHGEF2,
CC NOD2 and RIPK2. Interacts with ARHGEF2; the interaction mediates
CC tyrosine phosphorylation of RIPK2 by Src kinase CSK. Binds to
CC CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and
CC BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both
CC the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD1.
CC Interacts (via CARD domain) with NOD2 (via CARD domain)
CC (PubMed:19592251, PubMed:21887730, PubMed:27812135). Interacts with
CC MAP3K4; this interaction sequesters RIPK2 from the NOD2 signaling
CC pathway. Interacts with IKBKG/NEMO. The polyubiquitinated protein
CC interacts with MAP3K7/TAK1. Interacts with XIAP/BIRC4. Interacts with
CC NLRP10. Interacts with CARD9. Interacts with INAVA; the interaction
CC takes place upon PRR stimulation (PubMed:28436939). Interacts (via CARD
CC domain) with NGFR (via death domain) (PubMed:26646181).
CC {ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:18079694,
CC ECO:0000269|PubMed:18775659, ECO:0000269|PubMed:19592251,
CC ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:21931591,
CC ECO:0000269|PubMed:22672233, ECO:0000269|PubMed:26646181,
CC ECO:0000269|PubMed:27812135, ECO:0000269|PubMed:28436939}.
CC -!- INTERACTION:
CC O43353; Q13490: BIRC2; NbExp=3; IntAct=EBI-358522, EBI-514538;
CC O43353; Q13489: BIRC3; NbExp=3; IntAct=EBI-358522, EBI-517709;
CC O43353; Q9BX69: CARD6; NbExp=2; IntAct=EBI-358522, EBI-14405242;
CC O43353; Q7Z434: MAVS; NbExp=3; IntAct=EBI-358522, EBI-995373;
CC O43353; Q9HC29: NOD2; NbExp=3; IntAct=EBI-358522, EBI-7445625;
CC O43353; O43353: RIPK2; NbExp=6; IntAct=EBI-358522, EBI-358522;
CC O43353; Q12933: TRAF2; NbExp=2; IntAct=EBI-358522, EBI-355744;
CC O43353; Q13114: TRAF3; NbExp=6; IntAct=EBI-358522, EBI-357631;
CC O43353; P98170: XIAP; NbExp=21; IntAct=EBI-358522, EBI-517127;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21887730}.
CC Endoplasmic reticulum {ECO:0000269|PubMed:28656966}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43353-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O43353-2; Sequence=VSP_013266;
CC -!- TISSUE SPECIFICITY: Detected in heart, brain, placenta, lung,
CC peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas
CC and lymph node. {ECO:0000269|PubMed:9575181,
CC ECO:0000269|PubMed:9642260}.
CC -!- DOMAIN: Contains an N-terminal kinase domain and a C-terminal caspase
CC activation and recruitment domain (CARD) that mediates the recruitment
CC of CARD-containing proteins. {ECO:0000269|PubMed:26646181}.
CC -!- PTM: Autophosphorylated. Autophosphorylation at Tyr-474 is necessary
CC for effective NOD2 signaling. Phosphorylated. Phosphorylation at Tyr-
CC 381 by Src kinase CSK occurs in a ARHGEF2-dependent manner and is
CC required for NOD2-dependent innate immune activation.
CC {ECO:0000269|PubMed:16824733, ECO:0000269|PubMed:21123652,
CC ECO:0000269|PubMed:21887730}.
CC -!- PTM: Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked
CC polyubiquitination catalyzed by ITCH (PubMed:19592251,
CC PubMed:18079694). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked
CC chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-
CC kappa-B (PubMed:19464198, PubMed:21931591). Also undergoes 'Met-1'-
CC linked polyubiquitination; the head-to-tail linear polyubiquitination
CC is mediated by the LUBAC complex in response to NOD2 stimulation
CC (PubMed:23806334). Linear polyubiquitination is restricted by
CC FAM105B/otulin, probably to limit NOD2-dependent pro-inflammatory
CC signaling activation of NF-kappa-B (PubMed:23806334). Undergoes 'Lys-
CC 63'-linked deubiquitination by MYSM1 to attenuate NOD2-mediated
CC inflammation and tissue damage (By similarity). Ubiquitination at Lys-
CC 503 by ZNRF4 via 'Lys-48'-linked polyubiquitination promotes RIPK2
CC degradation by the proteasome; ubiquitination by ZNRF4 takes place
CC during both acute and NOD2 tolerance conditions (PubMed:28656966).
CC {ECO:0000250|UniProtKB:P58801, ECO:0000269|PubMed:18079694,
CC ECO:0000269|PubMed:19464198, ECO:0000269|PubMed:19592251,
CC ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:23806334,
CC ECO:0000269|PubMed:28656966}.
CC -!- PTM: (Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178
CC by Yersinia YopJ prevents phosphorylation and activation, thereby
CC promoting cell death. {ECO:0000269|PubMed:22520462}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
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DR EMBL; AF027706; AAC34970.1; -; mRNA.
DR EMBL; AF078530; AAC27722.1; -; mRNA.
DR EMBL; AF064824; AAC25668.1; -; mRNA.
DR EMBL; AY358813; AAQ89172.1; -; mRNA.
DR EMBL; AY358814; AAQ89173.1; -; mRNA.
DR EMBL; AK301448; BAH13484.1; -; mRNA.
DR EMBL; AC004003; AAC24561.1; -; Genomic_DNA.
DR EMBL; AF117829; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004553; AAH04553.1; -; mRNA.
DR CCDS; CCDS6247.1; -. [O43353-1]
DR RefSeq; NP_003812.1; NM_003821.5. [O43353-1]
DR RefSeq; XP_005251149.1; XM_005251092.3.
DR PDB; 2N7Z; NMR; -; A=434-539.
DR PDB; 2N83; NMR; -; B=434-539.
DR PDB; 4C8B; X-ray; 2.75 A; A/B=8-317.
DR PDB; 5AR2; X-ray; 2.44 A; A/B=1-310.
DR PDB; 5AR3; X-ray; 3.23 A; A/B=1-310.
DR PDB; 5AR4; X-ray; 2.70 A; A/B=1-310.
DR PDB; 5AR5; X-ray; 2.66 A; A/B=1-310.
DR PDB; 5AR7; X-ray; 2.71 A; A/B=1-310.
DR PDB; 5AR8; X-ray; 2.79 A; A/B=1-310.
DR PDB; 5J79; X-ray; 2.69 A; A/B=1-310.
DR PDB; 5J7B; X-ray; 2.53 A; A/B=1-310.
DR PDB; 5NG0; X-ray; 2.00 A; A/B=1-300.
DR PDB; 5NG2; X-ray; 2.80 A; A/B=1-300.
DR PDB; 5NG3; X-ray; 2.60 A; A/B/C/D=1-300.
DR PDB; 5W5J; X-ray; 2.85 A; A/B=2-311.
DR PDB; 5W5O; X-ray; 2.89 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=2-311.
DR PDB; 5YRN; EM; 4.10 A; A/B/C/D/E/F/G/H/I/J/K/L=434-540.
DR PDB; 6ES0; X-ray; 2.38 A; A/B=3-317.
DR PDB; 6FU5; X-ray; 3.26 A; A/B=3-317.
DR PDB; 6GFJ; X-ray; 3.30 A; A/B/C/D=435-540.
DR PDB; 6GGS; EM; 3.94 A; A/B/C/D/E/F/G/H/I/J=431-540.
DR PDB; 6HMX; X-ray; 2.53 A; A/B=1-310.
DR PDB; 6RN8; X-ray; 2.69 A; A/B=1-310.
DR PDB; 6RNA; X-ray; 2.62 A; A/B=1-310.
DR PDB; 6S1F; X-ray; 3.11 A; A/B/C/D=3-317.
DR PDB; 6SZE; X-ray; 2.94 A; A/B=1-310.
DR PDB; 6SZJ; X-ray; 2.53 A; A/B=1-310.
DR PDB; 6UL8; X-ray; 2.68 A; A/B=5-310.
DR PDBsum; 2N7Z; -.
DR PDBsum; 2N83; -.
DR PDBsum; 4C8B; -.
DR PDBsum; 5AR2; -.
DR PDBsum; 5AR3; -.
DR PDBsum; 5AR4; -.
DR PDBsum; 5AR5; -.
DR PDBsum; 5AR7; -.
DR PDBsum; 5AR8; -.
DR PDBsum; 5J79; -.
DR PDBsum; 5J7B; -.
DR PDBsum; 5NG0; -.
DR PDBsum; 5NG2; -.
DR PDBsum; 5NG3; -.
DR PDBsum; 5W5J; -.
DR PDBsum; 5W5O; -.
DR PDBsum; 5YRN; -.
DR PDBsum; 6ES0; -.
DR PDBsum; 6FU5; -.
DR PDBsum; 6GFJ; -.
DR PDBsum; 6GGS; -.
DR PDBsum; 6HMX; -.
DR PDBsum; 6RN8; -.
DR PDBsum; 6RNA; -.
DR PDBsum; 6S1F; -.
DR PDBsum; 6SZE; -.
DR PDBsum; 6SZJ; -.
DR PDBsum; 6UL8; -.
DR AlphaFoldDB; O43353; -.
DR SMR; O43353; -.
DR BioGRID; 114300; 70.
DR DIP; DIP-27518N; -.
DR IntAct; O43353; 27.
DR MINT; O43353; -.
DR STRING; 9606.ENSP00000220751; -.
DR BindingDB; O43353; -.
DR ChEMBL; CHEMBL5014; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; O43353; -.
DR GuidetoPHARMACOLOGY; 2190; -.
DR GlyGen; O43353; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O43353; -.
DR PhosphoSitePlus; O43353; -.
DR BioMuta; RIPK2; -.
DR EPD; O43353; -.
DR jPOST; O43353; -.
DR MassIVE; O43353; -.
DR MaxQB; O43353; -.
DR PaxDb; O43353; -.
DR PeptideAtlas; O43353; -.
DR PRIDE; O43353; -.
DR ProteomicsDB; 48908; -. [O43353-1]
DR ProteomicsDB; 48909; -. [O43353-2]
DR Antibodypedia; 12695; 678 antibodies from 45 providers.
DR DNASU; 8767; -.
DR Ensembl; ENST00000220751.5; ENSP00000220751.4; ENSG00000104312.8. [O43353-1]
DR GeneID; 8767; -.
DR KEGG; hsa:8767; -.
DR MANE-Select; ENST00000220751.5; ENSP00000220751.4; NM_003821.6; NP_003812.1.
DR UCSC; uc003yee.4; human. [O43353-1]
DR CTD; 8767; -.
DR DisGeNET; 8767; -.
DR GeneCards; RIPK2; -.
DR HGNC; HGNC:10020; RIPK2.
DR HPA; ENSG00000104312; Low tissue specificity.
DR MIM; 603455; gene.
DR neXtProt; NX_O43353; -.
DR OpenTargets; ENSG00000104312; -.
DR PharmGKB; PA34395; -.
DR VEuPathDB; HostDB:ENSG00000104312; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000156113; -.
DR HOGENOM; CLU_000288_7_35_1; -.
DR InParanoid; O43353; -.
DR OMA; CPVNHSW; -.
DR PhylomeDB; O43353; -.
DR TreeFam; TF106506; -.
DR BRENDA; 2.7.10.2; 2681.
DR BRENDA; 2.7.11.30; 2681.
DR PathwayCommons; O43353; -.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-202424; Downstream TCR signaling.
DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes.
DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-HSA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR SignaLink; O43353; -.
DR SIGNOR; O43353; -.
DR BioGRID-ORCS; 8767; 10 hits in 1119 CRISPR screens.
DR ChiTaRS; RIPK2; human.
DR GeneWiki; RIPK2; -.
DR GenomeRNAi; 8767; -.
DR Pharos; O43353; Tchem.
DR PRO; PR:O43353; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; O43353; protein.
DR Bgee; ENSG00000104312; Expressed in cartilage tissue and 173 other tissues.
DR ExpressionAtlas; O43353; baseline and differential.
DR Genevisible; O43353; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0031982; C:vesicle; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0050700; F:CARD domain binding; IDA:MGI.
DR GO; GO:0089720; F:caspase binding; IPI:UniProtKB.
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:0030274; F:LIM domain binding; IPI:UniProtKB.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0071225; P:cellular response to muramyl dipeptide; IDA:UniProtKB.
DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0033080; P:immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:2000563; P:positive regulation of CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0010942; P:positive regulation of cell death; IDA:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; IEA:Ensembl.
DR GO; GO:0001961; P:positive regulation of cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:MGI.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; NAS:BHF-UCL.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; NAS:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; NAS:BHF-UCL.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IMP:UniProtKB.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:UniProtKB.
DR GO; GO:0045627; P:positive regulation of T-helper 1 cell differentiation; IEA:Ensembl.
DR GO; GO:0002827; P:positive regulation of T-helper 1 type immune response; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; NAS:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:1904417; P:positive regulation of xenophagy; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IEA:Ensembl.
DR GO; GO:0070671; P:response to interleukin-12; IEA:Ensembl.
DR GO; GO:0070673; P:response to interleukin-18; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IDA:MGI.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IEA:Ensembl.
DR GO; GO:0098792; P:xenophagy; IEA:Ensembl.
DR CDD; cd08786; CARD_RIP2_CARD3; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR042149; CARD_RIP2.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017322; Rcpt-int_Ser/Thr_kinase-2.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF037921; STPK_RIP2; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; Alternative splicing;
KW Apoptosis; ATP-binding; Cytoplasm; Endoplasmic reticulum; Immunity;
KW Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Ubl conjugation.
FT CHAIN 1..540
FT /note="Receptor-interacting serine/threonine-protein kinase
FT 2"
FT /id="PRO_0000086608"
FT DOMAIN 18..294
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 432..524
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 338..369
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 338..368
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 146
FT /note="Proton acceptor"
FT /evidence="ECO:0000269|PubMed:9705938"
FT BINDING 24..32
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 47
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 149
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 168
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 174
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 176
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 176
FT /note="Phosphoserine; by autocatalysis; alternate"
FT /evidence="ECO:0000269|PubMed:16824733"
FT MOD_RES 178
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 181
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 183
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 189
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 363
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 363
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 381
FT /note="Phosphotyrosine; by CSK"
FT /evidence="ECO:0000269|PubMed:21887730"
FT MOD_RES 393
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 397
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 423
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 474
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:21123652"
FT MOD_RES 527
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 531
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 539
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195"
FT CROSSLNK 209
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:18079694"
FT CROSSLNK 503
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:28656966"
FT VAR_SEQ 1..137
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309,
FT ECO:0000303|PubMed:14702039"
FT /id="VSP_013266"
FT VARIANT 259
FT /note="I -> T (in dbSNP:rs2230801)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041045"
FT VARIANT 268
FT /note="L -> V (in dbSNP:rs35004667)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041046"
FT VARIANT 313
FT /note="K -> N (in dbSNP:rs35395048)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041047"
FT MUTAGEN 47
FT /note="K->A: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:9575181,
FT ECO:0000269|PubMed:9642260"
FT MUTAGEN 47
FT /note="K->M: Reduces FAS-mediated apoptosis."
FT /evidence="ECO:0000269|PubMed:9575181,
FT ECO:0000269|PubMed:9642260"
FT MUTAGEN 146
FT /note="D->N: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:9705938"
FT MUTAGEN 209
FT /note="K->R: Complete loss of polyubiquitination."
FT /evidence="ECO:0000269|PubMed:18079694"
FT MUTAGEN 381
FT /note="Y->A: Prevents phosphorylation. Reduces serine and
FT threonine phosphorylation of ARHGEF2."
FT /evidence="ECO:0000269|PubMed:21887730"
FT MUTAGEN 437
FT /note="Q->E: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT MUTAGEN 444
FT /note="R->E: Abolishes interaction with NOD1."
FT /evidence="ECO:0000269|PubMed:17054981"
FT MUTAGEN 467
FT /note="D->R: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT MUTAGEN 471
FT /note="K->E: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT MUTAGEN 474
FT /note="Y->F: Decreases interaction with NOD2."
FT /evidence="ECO:0000269|PubMed:21123652"
FT MUTAGEN 483
FT /note="R->E: Abolishes interaction with NOD1."
FT /evidence="ECO:0000269|PubMed:17054981"
FT MUTAGEN 488
FT /note="R->E: Abolishes interaction with NOD1."
FT /evidence="ECO:0000269|PubMed:17054981"
FT MUTAGEN 496
FT /note="I->A: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT MUTAGEN 500
FT /note="E->R: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT MUTAGEN 503
FT /note="K->R: Abolished ubiquitination by ZNRF4."
FT /evidence="ECO:0000269|PubMed:28656966"
FT MUTAGEN 528
FT /note="R->E: Decreased interaction with NGFR."
FT /evidence="ECO:0000269|PubMed:26646181"
FT CONFLICT 271
FT /note="S -> G (in Ref. 5; BAH13484)"
FT /evidence="ECO:0000305"
FT CONFLICT 514
FT /note="Q -> R (in Ref. 5; BAH13484)"
FT /evidence="ECO:0000305"
FT STRAND 7..9
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 15..17
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 18..26
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 31..37
FT /evidence="ECO:0007829|PDB:5NG0"
FT TURN 38..40
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 43..48
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 51..53
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 57..72
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 81..87
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 90..96
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 103..108
FT /evidence="ECO:0007829|PDB:5NG0"
FT TURN 110..112
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 118..136
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 138..140
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 149..151
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:5NG0"
FT STRAND 160..162
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 168..176
FT /evidence="ECO:0007829|PDB:5NG3"
FT TURN 189..192
FT /evidence="ECO:0007829|PDB:6ES0"
FT HELIX 195..197
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 202..205
FT /evidence="ECO:0007829|PDB:6ES0"
FT HELIX 210..224
FT /evidence="ECO:0007829|PDB:5NG0"
FT TURN 228..231
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 235..243
FT /evidence="ECO:0007829|PDB:5NG0"
FT TURN 252..254
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 262..272
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 277..279
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 283..295
FT /evidence="ECO:0007829|PDB:5NG0"
FT HELIX 300..312
FT /evidence="ECO:0007829|PDB:6ES0"
FT TURN 313..315
FT /evidence="ECO:0007829|PDB:6ES0"
FT HELIX 435..442
FT /evidence="ECO:0007829|PDB:6GFJ"
FT HELIX 444..450
FT /evidence="ECO:0007829|PDB:6GFJ"
FT HELIX 453..465
FT /evidence="ECO:0007829|PDB:6GFJ"
FT HELIX 471..478
FT /evidence="ECO:0007829|PDB:6GFJ"
FT STRAND 480..482
FT /evidence="ECO:0007829|PDB:6GFJ"
FT HELIX 483..497
FT /evidence="ECO:0007829|PDB:6GFJ"
FT HELIX 499..511
FT /evidence="ECO:0007829|PDB:6GFJ"
FT STRAND 526..528
FT /evidence="ECO:0007829|PDB:2N7Z"
FT TURN 530..532
FT /evidence="ECO:0007829|PDB:2N83"
SQ SEQUENCE 540 AA; 61195 MW; 575A692239505792 CRC64;
MNGEAICSAL PTIPYHKLAD LRYLSRGASG TVSSARHADW RVQVAVKHLH IHTPLLDSER
KDVLREAEIL HKARFSYILP ILGICNEPEF LGIVTEYMPN GSLNELLHRK TEYPDVAWPL
RFRILHEIAL GVNYLHNMTP PLLHHDLKTQ NILLDNEFHV KIADFGLSKW RMMSLSQSRS
SKSAPEGGTI IYMPPENYEP GQKSRASIKH DIYSYAVITW EVLSRKQPFE DVTNPLQIMY
SVSQGHRPVI NEESLPYDIP HRARMISLIE SGWAQNPDER PSFLKCLIEL EPVLRTFEEI
TFLEAVIQLK KTKLQSVSSA IHLCDKKKME LSLNIPVNHG PQEESCGSSQ LHENSGSPET
SRSLPAPQDN DFLSRKAQDC YFMKLHHCPG NHSWDSTISG SQRAAFCDHK TTPCSSAIIN
PLSTAGNSER LQPGIAQQWI QSKREDIVNQ MTEACLNQSL DALLSRDLIM KEDYELVSTK
PTRTSKVRQL LDTTDIQGEE FAKVIVQKLK DNKQMGLQPY PEILVVSRSP SLNLLQNKSM
