ID IRAK1_HUMAN Reviewed; 712 AA. AC P51617; D3DWW3; D3DWW4; Q7Z5V4; Q96C06; Q96RL2; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2000, sequence version 2. DT 27-MAR-2024, entry version 229. DE RecName: Full=Interleukin-1 receptor-associated kinase 1 {ECO:0000303|PubMed:16024789}; DE Short=IRAK-1 {ECO:0000303|PubMed:16024789}; DE EC=2.7.11.1; GN Name=IRAK1 {ECO:0000312|HGNC:HGNC:6112}; Synonyms=IRAK; 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), PARTIAL PROTEIN SEQUENCE, AND RP VARIANTS SER-196 AND LEU-532. RX PubMed=8599092; DOI=10.1126/science.271.5252.1128; RA Cao Z., Henzel W.J., Gao X.; RT "IRAK: a kinase associated with the interleukin-1 receptor."; RL Science 271:1128-1131(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=10723722; DOI=10.1007/s003350010035; RA Reichwald K., Thiesen J., Wiehe T., Weitzel J., Poustka W.A., Rosenthal A., RA Platzer M., Stratling W.H., Kioschis P.; RT "Comparative sequence analysis of the MECP2-locus in human and mouse RT reveals new transcribed regions."; RL Mamm. Genome 11:182-190(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, AND RP PHOSPHORYLATION. RX PubMed=11397809; DOI=10.1074/jbc.m103815200; RA Jensen L.E., Whitehead A.S.; RT "IRAK1b, a novel alternative splice variant of interleukin-1 receptor- RT associated kinase (IRAK), mediates interleukin-1 signaling and has RT prolonged stability."; RL J. Biol. Chem. 276:29037-29044(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RX PubMed=16024789; DOI=10.1128/mcb.25.15.6521-6532.2005; RA Rao N., Nguyen S., Ngo K., Fung-Leung W.P.; RT "A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase RT 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory RT signaling."; RL Mol. Cell. Biol. 25:6521-6532(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C., RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., RA Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). RC TISSUE=Placenta; 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 INTERACTION WITH MYD88. RX PubMed=9430229; DOI=10.1016/s1074-7613(00)80402-1; RA Wesche H., Henzel W.J., Shillinglaw W., Li S., Cao Z.; RT "MyD88: an adapter that recruits IRAK to the IL-1 receptor complex."; RL Immunity 7:837-847(1997). RN [9] RP INTERACTION WITH TOLLIP. RX PubMed=10854325; DOI=10.1038/35014038; RA Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C., Maschera B., RA Lewis A., Ray K., Tschopp J., Volpe F.; RT "Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1 RT receptor."; RL Nat. Cell Biol. 2:346-351(2000). RN [10] RP INTERACTION WITH IRAK4. RX PubMed=11960013; DOI=10.1073/pnas.082100399; RA Li S., Strelow A., Fontana E.J., Wesche H.; RT "IRAK4: a novel member of the IRAK family with the properties of an IRAK- RT kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002). RN [11] RP INTERACTION WITH PELI1 AND TRAF6. RX PubMed=12496252; DOI=10.1074/jbc.m212112200; RA Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X.; RT "Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through RT its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK- RT tumor necrosis factor receptor-associated factor 6 (TRAF6) complex."; RL J. Biol. Chem. 278:10952-10956(2003). RN [12] RP FUNCTION IN PHOSPHORYLATION OF PELI2. RX PubMed=12860405; DOI=10.1016/s0014-5793(03)00697-5; RA Strelow A., Kollewe C., Wesche H.; RT "Characterization of Pellino2, a substrate of IRAK1 and IRAK4."; RL FEBS Lett. 547:157-161(2003). RN [13] RP PHOSPHORYLATION BY IRAK4. RX PubMed=12538665; DOI=10.1084/jem.20021790; RA Burns K., Janssens S., Brissoni B., Olivos N., Beyaert R., Tschopp J.; RT "Inhibition of interleukin 1 receptor/Toll-like receptor signaling through RT the alternatively spliced, short form of MyD88 is due to its failure to RT recruit IRAK-4."; RL J. Exp. Med. 197:263-268(2003). RN [14] RP INTERACTION WITH PELI3. RX PubMed=12874243; DOI=10.4049/jimmunol.171.3.1500; RA Jensen L.E., Whitehead A.S.; RT "Pellino3, a novel member of the Pellino protein family, promotes RT activation of c-Jun and Elk-1 and may act as a scaffolding protein."; RL J. Immunol. 171:1500-1506(2003). RN [15] RP FUNCTION, AND PHOSPHORYLATION AT THR-66. RX PubMed=14684752; DOI=10.1074/jbc.c300431200; RA Mamidipudi V., Lin C., Seibenhener M.L., Wooten M.W.; RT "Regulation of interleukin receptor-associated kinase (IRAK) RT phosphorylation and signaling by iota protein kinase C."; RL J. Biol. Chem. 279:4161-4165(2004). RN [16] RP PHOSPHORYLATION AT THR-209 AND THR-387, DOMAIN, AND MUTAGENESIS OF THR-209 RP AND THR-387. RX PubMed=14625308; DOI=10.1074/jbc.m309251200; RA Kollewe C., Mackensen A.C., Neumann D., Knop J., Cao P., Li S., Wesche H., RA Martin M.U.; RT "Sequential autophosphorylation steps in the interleukin-1 receptor- RT associated kinase-1 regulate its availability as an adapter in interleukin- RT 1 signaling."; RL J. Biol. Chem. 279:5227-5236(2004). RN [17] RP FUNCTION, AND MUTAGENESIS OF LYS-239. RX PubMed=15084582; DOI=10.1074/jbc.m400785200; RA Qin J., Jiang Z., Qian Y., Casanova J.-L., Li X.; RT "IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor- RT associated kinase phosphorylation and IL-1 responsiveness."; RL J. Biol. Chem. 279:26748-26753(2004). RN [18] RP FUNCTION IN PHOSPHORYLATION OF STAT3. RX PubMed=15465816; DOI=10.1074/jbc.m410369200; RA Huang Y., Li T., Sane D.C., Li L.; RT "IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced RT interleukin-10 gene expression."; RL J. Biol. Chem. 279:51697-51703(2004). RN [19] RP INTERACTION WITH IL1RL1. RX PubMed=16286016; DOI=10.1016/j.immuni.2005.09.015; RA Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K., RA Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F., RA Kastelein R.A.; RT "IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor- RT related protein ST 2 and induces T helper type 2-associated cytokines."; RL Immunity 23:479-490(2005). RN [20] RP FUNCTION IN PHOSPHORYLATION OF IRF7. RX PubMed=15767370; DOI=10.1084/jem.20042372; RA Uematsu S., Sato S., Yamamoto M., Hirotani T., Kato H., Takeshita F., RA Matsuda M., Coban C., Ishii K.J., Kawai T., Takeuchi O., Akira S.; RT "Interleukin-1 receptor-associated kinase-1 plays an essential role for RT Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} RT induction."; RL J. Exp. Med. 201:915-923(2005). RN [21] RP IDENTIFICATION IN COMPLEX WITH IRAK4; MYD88; PELI1 AND TRAF6. RX PubMed=16951688; DOI=10.1038/ni1383; RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S., RA Kim I.H., Kim S.J., Park S.H.; RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor RT signaling through direct interaction with the adapter Pellino-1."; RL Nat. Immunol. 7:1057-1065(2006). RN [22] RP SUMOYLATION, AND SUBCELLULAR LOCATION. RX PubMed=16690127; DOI=10.1016/j.molimm.2006.03.021; RA Su J., Richter K., Zhang C., Gu Q., Li L.; RT "Differential regulation of interleukin-1 receptor associated kinase 1 RT (IRAK1) splice variants."; RL Mol. Immunol. 44:900-905(2007). RN [23] RP FUNCTION IN PHOSPHORYLATION OF PELI1. RX PubMed=17997719; DOI=10.1042/bj20071365; RA Ordureau A., Smith H., Windheim M., Peggie M., Carrick E., Morrice N., RA Cohen P.; RT "The IRAK-catalysed activation of the E3 ligase function of Pellino RT isoforms induces the Lys63-linked polyubiquitination of IRAK1."; RL Biochem. J. 409:43-52(2008). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, AND IDENTIFICATION BY RP 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 [25] RP UBIQUITINATION AT LYS-134 AND LYS-180 BY TRAF6, AND INTERACTION WITH RP IKBKG/NEMO. RX PubMed=18347055; DOI=10.1128/mcb.02098-07; RA Conze D.B., Wu C.J., Thomas J.A., Landstrom A., Ashwell J.D.; RT "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 RT receptor- and toll-like receptor-mediated NF-kappaB activation."; RL Mol. Cell. Biol. 28:3538-3547(2008). RN [26] RP IDENTIFICATION BY 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 [27] RP UBIQUITINATION. RX PubMed=19675569; DOI=10.1038/nature08247; RA Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., RA Chen Z.J.; RT "Direct activation of protein kinases by unanchored polyubiquitin chains."; RL Nature 461:114-119(2009). RN [28] RP FUNCTION IN PHOSPHORYLATION OF TIRAP. RX PubMed=20400509; DOI=10.1074/jbc.m109.098137; RA Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H., RA Morrice N., O'Neill L.A.; RT "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation RT of MyD88 adaptor-like (Mal)."; RL J. Biol. Chem. 285:18276-18282(2010). RN [29] RP REVIEW ON FUNCTION. RX PubMed=17890055; DOI=10.1016/j.cellsig.2007.08.009; RA Gottipati S., Rao N.L., Fung-Leung W.P.; RT "IRAK1: a critical signaling mediator of innate immunity."; RL Cell. Signal. 20:269-276(2008). RN [30] RP INTERACTION WITH NFATC4, AND MUTAGENESIS OF ASP-340. RX PubMed=18691762; DOI=10.1016/j.molimm.2008.06.023; RA Wang D., Fasciano S., Li L.; RT "The interleukin-1 receptor associated kinase 1 contributes to the RT regulation of NFAT."; RL Mol. Immunol. 45:3902-3908(2008). RN [31] RP REVIEW ON FUNCTION. RX PubMed=19022706; DOI=10.1016/j.it.2008.10.001; RA Moynagh P.N.; RT "The Pellino family: IRAK E3 ligases with emerging roles in innate immune RT signalling."; RL Trends Immunol. 30:33-42(2009). RN [32] 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 [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-371; SER-375 AND SER-556, AND RP 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 [34] 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 [35] RP INTERACTION WITH MUMPS VIRUS PROTEIN SH. 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 [36] 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 [37] RP INTERACTION WITH ALPHAVIRUS CAPSID PROTEINS (MICROBIAL INFECTION). RX PubMed=33673546; DOI=10.3390/v13030377; RA Landers V.D., Wilkey D.W., Merchant M.L., Mitchell T.C., Sokoloski K.J.; RT "The Alphaviral Capsid Protein Inhibits IRAK1-Dependent TLR Signaling."; RL Viruses 13:0-0(2021). RN [38] RP VARIANTS [LARGE SCALE ANALYSIS] MET-398; MET-412; HIS-421; LEU-532; RP SER-619; MET-625; TRP-638 AND GLY-690. 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-protein kinase that plays a critical role in CC initiating innate immune response against foreign pathogens. Involved CC in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly CC recruited by MYD88 to the receptor-signaling complex upon TLR CC activation. Association with MYD88 leads to IRAK1 phosphorylation by CC IRAK4 and subsequent autophosphorylation and kinase activation. CC Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and CC PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, CC the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated CC IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the CC NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA CC and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and CC activation. Alternatively, phosphorylates TIRAP to promote its CC ubiquitination and subsequent degradation. Phosphorylates the CC interferon regulatory factor 7 (IRF7) to induce its activation and CC translocation to the nucleus, resulting in transcriptional activation CC of type I IFN genes, which drive the cell in an antiviral state. When CC sumoylated, translocates to the nucleus and phosphorylates STAT3. CC {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405, CC ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582, CC ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370, CC ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}. 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 -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC -!- SUBUNIT: Homodimer (By similarity). Forms a complex with TRAF6, PELI1, CC IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 CC prevents complex formation and hence negatively regulates IL1R-TLR CC signaling and eventually NF-kappa-B-mediated gene expression CC (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits CC MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation CC (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the CC stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; CC this interaction occurs in the cytosol prior to receptor activation CC (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts CC with PELI1 and TRAF6 (PubMed:12496252). Interacts (when CC polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with CC RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). CC Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this CC interaction increases the interaction between ZC3H12A and IKBKB/IKKB CC (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with CC PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes CC place upon PRR stimulation (PubMed:28436939). Interacts (via C- CC terminus) with NFATC4 (via N-terminus) (PubMed:18691762). CC {ECO:0000250|UniProtKB:Q62406, ECO:0000269|PubMed:10854325, CC ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12496252, CC ECO:0000269|PubMed:12874243, ECO:0000269|PubMed:16286016, CC ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:18347055, CC ECO:0000269|PubMed:18691762, ECO:0000269|PubMed:28436939, CC ECO:0000269|PubMed:29883609, ECO:0000269|PubMed:9430229}. 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 alphaviruses SINV, CHIKV, CC RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition CC of IRAK1-dependent signaling. {ECO:0000269|PubMed:33673546}. CC -!- INTERACTION: CC P51617; Q15306: IRF4; NbExp=2; IntAct=EBI-358664, EBI-751345; CC P51617; Q92985: IRF7; NbExp=2; IntAct=EBI-358664, EBI-968267; CC P51617; Q99836: MYD88; NbExp=3; IntAct=EBI-358664, EBI-447677; CC P51617; Q96FA3: PELI1; NbExp=4; IntAct=EBI-358664, EBI-448369; CC P51617; Q9HAT8: PELI2; NbExp=4; IntAct=EBI-358664, EBI-448407; CC P51617; Q8N2H9-2: PELI3; NbExp=2; IntAct=EBI-358664, EBI-448472; CC P51617; Q13526: PIN1; NbExp=10; IntAct=EBI-358664, EBI-714158; CC P51617; Q86WV6: STING1; NbExp=2; IntAct=EBI-358664, EBI-2800345; CC P51617; P58753: TIRAP; NbExp=2; IntAct=EBI-358664, EBI-528644; CC P51617; Q9Y4K3: TRAF6; NbExp=3; IntAct=EBI-358664, EBI-359276; CC P51617; Q8VCW4: Unc93b1; Xeno; NbExp=2; IntAct=EBI-358664, EBI-6116986; CC P51617; Q5D1E7: Zc3h12a; Xeno; NbExp=3; IntAct=EBI-358664, EBI-5326026; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16690127}. Nucleus CC {ECO:0000269|PubMed:16690127}. Lipid droplet {ECO:0000250}. CC Note=Translocates to the nucleus when sumoylated. RSAD2/viperin CC recruits it to the lipid droplet (By similarity). {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=a; CC IsoId=P51617-1; Sequence=Displayed; CC Name=2; Synonyms=b; CC IsoId=P51617-2; Sequence=VSP_011851; CC Name=3; CC IsoId=P51617-3; Sequence=VSP_011849, VSP_011850, VSP_011851; CC Name=4; CC IsoId=P51617-4; Sequence=VSP_041950; CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are ubiquitously expressed CC in all tissues examined, with isoform 1 being more strongly expressed CC than isoform 2. {ECO:0000269|PubMed:11397809}. CC -!- DOMAIN: The ProST region is composed of many proline and serine CC residues (more than 20 of each) and some threonines. This region is the CC site of IRAK-1 hyperphosphorylation. {ECO:0000269|PubMed:14625308}. CC -!- PTM: Following recruitment on the activated receptor complex, CC phosphorylated on Thr-209, probably by IRAK4, resulting in a CC conformational change of the kinase domain, allowing further CC phosphorylations to take place. Thr-387 phosphorylation in the CC activation loop is required to achieve full enzymatic activity. CC {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12538665, CC ECO:0000269|PubMed:14625308, ECO:0000269|PubMed:14684752}. CC -!- PTM: Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta CC by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin CC chains linked through 'Lys-63'. Ubiquitination promotes interaction CC with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation. CC {ECO:0000269|PubMed:16690127, ECO:0000269|PubMed:18347055, CC ECO:0000269|PubMed:19675569}. CC -!- MISCELLANEOUS: [Isoform 2]: Inactive. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. Pelle subfamily. {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; L76191; AAC41949.1; -; mRNA. DR EMBL; AF030876; AAC08756.1; -; Genomic_DNA. DR EMBL; AF346607; AAK62888.1; -; mRNA. DR EMBL; DQ054788; AAY88246.1; -; mRNA. DR EMBL; U52112; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471172; EAW72762.1; -; Genomic_DNA. DR EMBL; CH471172; EAW72763.1; -; Genomic_DNA. DR EMBL; CH471172; EAW72764.1; -; Genomic_DNA. DR EMBL; CH471172; EAW72765.1; -; Genomic_DNA. DR EMBL; BC054000; AAH54000.1; -; mRNA. DR EMBL; BC014963; AAH14963.1; -; mRNA. DR CCDS; CCDS14740.1; -. [P51617-1] DR CCDS; CCDS35443.1; -. [P51617-4] DR CCDS; CCDS35444.1; -. [P51617-2] DR PIR; G02512; G02512. DR RefSeq; NP_001020413.1; NM_001025242.1. [P51617-2] DR RefSeq; NP_001020414.1; NM_001025243.1. [P51617-4] DR RefSeq; NP_001560.2; NM_001569.3. [P51617-1] DR PDB; 6BFN; X-ray; 2.26 A; A/B=194-530. DR PDBsum; 6BFN; -. DR AlphaFoldDB; P51617; -. DR SMR; P51617; -. DR BioGRID; 109863; 349. DR CORUM; P51617; -. DR DIP; DIP-397N; -. DR ELM; P51617; -. DR IntAct; P51617; 190. DR MINT; P51617; -. DR STRING; 9606.ENSP00000358997; -. DR BindingDB; P51617; -. DR ChEMBL; CHEMBL3357; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; P51617; -. DR GuidetoPHARMACOLOGY; 2042; -. DR GlyGen; P51617; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P51617; -. DR PhosphoSitePlus; P51617; -. DR BioMuta; IRAK1; -. DR DMDM; 8928535; -. DR CPTAC; CPTAC-2897; -. DR CPTAC; CPTAC-2898; -. DR EPD; P51617; -. DR jPOST; P51617; -. DR MassIVE; P51617; -. DR MaxQB; P51617; -. DR PaxDb; 9606-ENSP00000358997; -. DR PeptideAtlas; P51617; -. DR ProteomicsDB; 56349; -. [P51617-1] DR ProteomicsDB; 56350; -. [P51617-2] DR ProteomicsDB; 56351; -. [P51617-3] DR ProteomicsDB; 56352; -. [P51617-4] DR Pumba; P51617; -. DR Antibodypedia; 3845; 1274 antibodies from 47 providers. DR DNASU; 3654; -. DR Ensembl; ENST00000369974.6; ENSP00000358991.2; ENSG00000184216.15. [P51617-4] DR Ensembl; ENST00000369980.8; ENSP00000358997.3; ENSG00000184216.15. [P51617-1] DR Ensembl; ENST00000393687.6; ENSP00000377291.2; ENSG00000184216.15. [P51617-2] DR GeneID; 3654; -. DR KEGG; hsa:3654; -. DR MANE-Select; ENST00000369980.8; ENSP00000358997.3; NM_001569.4; NP_001560.2. DR UCSC; uc004fjr.2; human. [P51617-1] DR AGR; HGNC:6112; -. DR CTD; 3654; -. DR DisGeNET; 3654; -. DR GeneCards; IRAK1; -. DR HGNC; HGNC:6112; IRAK1. DR HPA; ENSG00000184216; Low tissue specificity. DR MalaCards; IRAK1; -. DR MIM; 300283; gene. DR neXtProt; NX_P51617; -. DR OpenTargets; ENSG00000184216; -. DR Orphanet; 93552; Pediatric systemic lupus erythematosus. DR Orphanet; 536; Systemic lupus erythematosus. DR PharmGKB; PA29912; -. DR VEuPathDB; HostDB:ENSG00000184216; -. DR eggNOG; KOG1187; Eukaryota. DR GeneTree; ENSGT00940000160502; -. DR HOGENOM; CLU_000288_173_1_1; -. DR InParanoid; P51617; -. DR OMA; PIAIQIY; -. DR OrthoDB; 2999496at2759; -. DR PhylomeDB; P51617; -. DR TreeFam; TF328924; -. DR BRENDA; 2.7.10.2; 2681. DR PathwayCommons; P51617; -. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane. DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-HSA-209543; p75NTR recruits signalling complexes. [P51617-1] DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. 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-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-HSA-8986944; Transcriptional Regulation by MECP2. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-937039; IRAK1 recruits IKK complex. DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses. DR Reactome; R-HSA-975110; TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling. DR Reactome; R-HSA-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation. DR Reactome; R-HSA-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation. DR Reactome; R-HSA-975155; MyD88 dependent cascade initiated on endosome. DR Reactome; R-HSA-975871; MyD88 cascade initiated on plasma membrane. DR SignaLink; P51617; -. DR SIGNOR; P51617; -. DR BioGRID-ORCS; 3654; 20 hits in 816 CRISPR screens. DR ChiTaRS; IRAK1; human. DR GeneWiki; IRAK1; -. DR GenomeRNAi; 3654; -. DR Pharos; P51617; Tchem. DR PRO; PR:P51617; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; P51617; Protein. DR Bgee; ENSG00000184216; Expressed in parotid gland and 203 other cell types or tissues. DR ExpressionAtlas; P51617; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProt. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0031072; F:heat shock protein binding; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0016301; F:kinase activity; IDA:MGI. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:BHF-UCL. DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL. DR GO; GO:0004672; F:protein kinase activity; IDA:MGI. DR GO; GO:0019901; F:protein kinase binding; IPI: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:0007249; P:canonical NF-kappaB signal transduction; IMP:ARUK-UCL. DR GO; GO:0034605; P:cellular response to heat; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central. DR GO; GO:0045087; P:innate immune response; IBA:GO_Central. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IDA:UniProt. DR GO; GO:0038172; P:interleukin-33-mediated signaling pathway; IMP:UniProt. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:BHF-UCL. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:BHF-UCL. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IMP:MGI. DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IMP:ARUK-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0032481; P:positive regulation of type I interferon production; IMP:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL. DR GO; GO:0001959; P:regulation of cytokine-mediated signaling pathway; IMP:BHF-UCL. DR GO; GO:0070555; P:response to interleukin-1; IMP:BHF-UCL. DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:BHF-UCL. DR GO; GO:0008063; P:Toll signaling pathway; IBA:GO_Central. DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IMP:BHF-UCL. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IBA:GO_Central. DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome. DR GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; IMP:BHF-UCL. DR CDD; cd08794; Death_IRAK1; 1. DR DisProt; DP02467; -. 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; IPR035533; Death_IRAK1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR47989; OS01G0750732 PROTEIN; 1. DR PANTHER; PTHR47989:SF47; SERINE_THREONINE-PROTEIN KINASE PBL28-RELATED; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P51617; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasm; KW Direct protein sequencing; Host-virus interaction; Immunity; KW Innate immunity; Isopeptide bond; Kinase; Lipid droplet; Magnesium; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Ubl conjugation. FT CHAIN 1..712 FT /note="Interleukin-1 receptor-associated kinase 1" FT /id="PRO_0000086030" FT DOMAIN 27..106 FT /note="Death" FT DOMAIN 212..521 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 105..187 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 110..211 FT /note="ProST region" FT REGION 532..591 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 613..660 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 690..712 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 134..151 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 163..179 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 538..556 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 572..590 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 646..660 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 340 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 218..226 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 239 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT BINDING 342..345 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 358 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 66 FT /note="Phosphothreonine; by PKC/PRKCI" FT /evidence="ECO:0000269|PubMed:14684752" FT MOD_RES 131 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 209 FT /note="Phosphothreonine; by IRAK4" FT /evidence="ECO:0000305|PubMed:14625308" FT MOD_RES 371 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 375 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 387 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:14625308" FT MOD_RES 556 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CROSSLNK 134 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:18347055" FT CROSSLNK 180 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:18347055" FT VAR_SEQ 45 FT /note="F -> FGGWRRAAGGREARGLLAPTPDAPRPA (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011849" FT VAR_SEQ 435..513 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16024789" FT /id="VSP_041950" FT VAR_SEQ 478..492 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_011850" FT VAR_SEQ 513..542 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:11397809, FT ECO:0000303|PubMed:15489334" FT /id="VSP_011851" FT VARIANT 194 FT /note="R -> H (in dbSNP:rs11465830)" FT /id="VAR_051629" FT VARIANT 196 FT /note="F -> S (in dbSNP:rs1059702)" FT /evidence="ECO:0000269|PubMed:8599092" FT /id="VAR_051630" FT VARIANT 203 FT /note="C -> S (in dbSNP:rs10127175)" FT /id="VAR_051631" FT VARIANT 398 FT /note="T -> M (in dbSNP:rs56340948)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040573" FT VARIANT 412 FT /note="V -> M (in a glioblastoma multiforme sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040574" FT VARIANT 421 FT /note="Q -> H (in a breast pleomorphic lobular carcinoma FT sample; somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040575" FT VARIANT 532 FT /note="S -> L (in dbSNP:rs1059703)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:8599092" FT /id="VAR_040576" FT VARIANT 619 FT /note="G -> S (in dbSNP:rs34112487)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040577" FT VARIANT 625 FT /note="T -> M (in dbSNP:rs35638718)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040578" FT VARIANT 638 FT /note="R -> W (in dbSNP:rs56082801)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040579" FT VARIANT 690 FT /note="S -> G (in a lung adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040580" FT MUTAGEN 209 FT /note="T->A: Completely abolishes auto-phosphorylation in FT the kinase domain." FT /evidence="ECO:0000269|PubMed:14625308" FT MUTAGEN 239 FT /note="K->S: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:15084582" FT MUTAGEN 340 FT /note="D->N: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:18691762" FT MUTAGEN 387 FT /note="T->A: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:14625308" FT STRAND 195..197 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 202..209 FT /evidence="ECO:0007829|PDB:6BFN" FT TURN 210..212 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 217..220 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 222..231 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 234..241 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 249..265 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 274..280 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 283..289 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 296..301 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 304..307 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 312..331 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 332..334 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 345..348 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 354..356 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 359..361 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 388..390 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 393..397 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 403..419 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 423..427 FT /evidence="ECO:0007829|PDB:6BFN" FT STRAND 430..433 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 434..436 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 437..445 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 464..466 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 467..476 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 487..500 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 505..507 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 511..521 FT /evidence="ECO:0007829|PDB:6BFN" FT HELIX 522..524 FT /evidence="ECO:0007829|PDB:6BFN" SQ SEQUENCE 712 AA; 76537 MW; A7ADED75D3A3981D CRC64; MAGGPGPGEP AAPGAQHFLY EVPPWVMCRF YKVMDALEPA DWCQFAALIV RDQTELRLCE RSGQRTASVL WPWINRNARV ADLVHILTHL QLLRARDIIT AWHPPAPLPS PGTTAPRPSS IPAPAEAEAW SPRKLPSSAS TFLSPAFPGS QTHSGPELGL VPSPASLWPP PPSPAPSSTK PGPESSVSLL QGARPFPFCW PLCEISRGTH NFSEELKIGE GGFGCVYRAV MRNTVYAVKR LKENADLEWT AVKQSFLTEV EQLSRFRHPN IVDFAGYCAQ NGFYCLVYGF LPNGSLEDRL HCQTQACPPL SWPQRLDILL GTARAIQFLH QDSPSLIHGD IKSSNVLLDE RLTPKLGDFG LARFSRFAGS SPSQSSMVAR TQTVRGTLAY LPEEYIKTGR LAVDTDTFSF GVVVLETLAG QRAVKTHGAR TKYLKDLVEE EAEEAGVALR STQSTLQAGL AADAWAAPIA MQIYKKHLDP RPGPCPPELG LGLGQLACCC LHRRAKRRPP MTQVYERLEK LQAVVAGVPG HSEAASCIPP SPQENSYVSS TGRAHSGAAP WQPLAAPSGA SAQAAEQLQR GPNQPVESDE SLGGLSAALR SWHLTPSCPL DPAPLREAGC PQGDTAGESS WGSGPGSRPT AVEGLALGSS ASSSSEPPQI IINPARQKMV QKLALYEDGA LDSLQLLSSS SLPGLGLEQD RQGPEESDEF QS //