ID M3K7_HUMAN Reviewed; 606 AA.
AC O43318; B2RE27; E1P523; O43317; O43319; Q5TDN2; Q5TDN3; Q5TDT7; Q9NTR3;
AC Q9NZ70;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 27-MAR-2024, entry version 239.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 7;
DE EC=2.7.11.25 {ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:10838074, ECO:0000269|PubMed:12589052};
DE AltName: Full=Transforming growth factor-beta-activated kinase 1;
DE Short=TGF-beta-activated kinase 1;
GN Name=MAP3K7 {ECO:0000303|PubMed:28397838, ECO:0000312|HGNC:HGNC:6859};
GN Synonyms=TAK1;
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] (ISOFORMS 1A; 1B AND 1C).
RC TISSUE=Lung;
RX PubMed=9480845; DOI=10.1006/bbrc.1998.8124;
RA Sakurai H., Shigemori N., Hasegawa K., Sugita T.;
RT "TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-
RT kappa B-inducing kinase-independent mechanism.";
RL Biochem. Biophys. Res. Commun. 243:545-549(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1D), AND TISSUE SPECIFICITY.
RX PubMed=11118615; DOI=10.1016/s0167-4781(00)00258-x;
RA Dempsey C.E., Sakurai H., Sugita T., Guesdon F.;
RT "Alternative splicing and gene structure of the transforming growth factor
RT beta-activated kinase 1.";
RL Biochim. Biophys. Acta 1517:46-52(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1A).
RC TISSUE=Trachea;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE 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] (ISOFORM 1A).
RC TISSUE=Uterus;
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 IN PHOSPHORYLATION OF MAP2K3/MKK3 AND MAP2K6/MKK6.
RX PubMed=8663074; DOI=10.1074/jbc.271.23.13675;
RA Moriguchi T., Kuroyanagi N., Yamaguchi K., Gotoh Y., Irie K., Kano T.,
RA Shirakabe K., Muro Y., Shibuya H., Matsumoto K., Nishida E., Hagiwara M.;
RT "A novel kinase cascade mediated by mitogen-activated protein kinase kinase
RT 6 and MKK3.";
RL J. Biol. Chem. 271:13675-13679(1996).
RN [9]
RP INTERACTION WITH TAB1/MAP3K7IP1.
RX PubMed=8638164; DOI=10.1126/science.272.5265.1179;
RA Shibuya H., Yamaguchi K., Shirakabe K., Tonegawa A., Gotoh Y., Ueno N.,
RA Irie K., Nishida E., Matsumoto K.;
RT "TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction.";
RL Science 272:1179-1182(1996).
RN [10]
RP ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=9079627; DOI=10.1074/jbc.272.13.8141;
RA Shirakabe K., Yamaguchi K., Shibuya H., Irie K., Matsuda S., Moriguchi T.,
RA Gotoh Y., Matsumoto K., Nishida E.;
RT "TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-
RT Jun N-terminal kinase.";
RL J. Biol. Chem. 272:8141-8144(1997).
RN [11]
RP INTERACTION WITH TRAF6 AND TAB1/MAP3K7IP1, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=10094049; DOI=10.1038/18465;
RA Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J., Cao Z., Matsumoto K.;
RT "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase
RT cascade in the IL-1 signalling pathway.";
RL Nature 398:252-256(1999).
RN [12]
RP INTERACTION WITH TAB1, PHOSPHORYLATION AT THR-184; THR-187 AND SER-192,
RP ACTIVATION, AND CATALYTIC ACTIVITY.
RX PubMed=10838074; DOI=10.1016/s0014-5793(00)01588-x;
RA Sakurai H., Miyoshi H., Mizukami J., Sugita T.;
RT "Phosphorylation-dependent activation of TAK1 mitogen-activated protein
RT kinase kinase kinase by TAB1.";
RL FEBS Lett. 474:141-145(2000).
RN [13]
RP PHOSPHORYLATION AT SER-192, AND ACTIVITY REGULATION.
RX PubMed=10702308; DOI=10.1074/jbc.275.10.7359;
RA Kishimoto K., Matsumoto K., Ninomiya-Tsuji J.;
RT "TAK1 mitogen-activated protein kinase kinase kinase is activated by
RT autophosphorylation within its activation loop.";
RL J. Biol. Chem. 275:7359-7364(2000).
RN [14]
RP ACTIVITY REGULATION, DEPHOSPHORYLATION BY PPM1B/PP2CB, AND INTERACTION WITH
RP PPM1B/PP2CB.
RX PubMed=11104763; DOI=10.1074/jbc.m007773200;
RA Hanada M., Ninomiya-Tsuji J., Komaki K., Ohnishi M., Katsura K.,
RA Kanamaru R., Matsumoto K., Tamura S.;
RT "Regulation of the TAK1 signaling pathway by protein phosphatase 2C.";
RL J. Biol. Chem. 276:5753-5759(2001).
RN [15]
RP UBIQUITINATION, FUNCTION, ACTIVITY REGULATION, INTERACTION WITH
RP TAB1/MAP3K7IP2 AND TAB2/MAP3K7IP2, AND IDENTIFICATION IN THE TRIKA2
RP COMPLEX.
RX PubMed=11460167; DOI=10.1038/35085597;
RA Wang C., Deng L., Hong M., Akkaraju G.R., Inoue J., Chen Z.J.;
RT "TAK1 is a ubiquitin-dependent kinase of MKK and IKK.";
RL Nature 412:346-351(2001).
RN [16]
RP INTERACTION WITH IRAK; TAB1/MAP3K7IP1; TAB2/MAP3K7IP2 AND TRAF6,
RP PHOSPHORYLATION, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=12242293; DOI=10.1128/mcb.22.20.7158-7167.2002;
RA Jiang Z., Ninomiya-Tsuji J., Qian Y., Matsumoto K., Li X.;
RT "Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced
RT signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and
RT activate TAK1 in the cytosol.";
RL Mol. Cell. Biol. 22:7158-7167(2002).
RN [17]
RP INTERACTION WITH PELI1 AND PELI2.
RX PubMed=12804775; DOI=10.1016/s0014-5793(03)00533-7;
RA Jensen L.E., Whitehead A.S.;
RT "Pellino2 activates the mitogen activated protein kinase pathway.";
RL FEBS Lett. 545:199-202(2003).
RN [18]
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 [19]
RP FUNCTION, INTERACTION WITH SMAD7; MAP2K3 AND P38 KINASE, MUTAGENESIS OF
RP LYS-63, AND CATALYTIC ACTIVITY.
RX PubMed=12589052; DOI=10.1091/mbc.02-03-0037;
RA Edlund S., Bu S., Schuster N., Aspenstroem P., Heuchel R., Heldin N.E.,
RA ten Dijke P., Heldin C.H., Landstrom M.;
RT "Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate
RT cancer cells involves Smad7-dependent activation of p38 by TGF-beta-
RT activated kinase 1 and mitogen-activated protein kinase kinase 3.";
RL Mol. Biol. Cell 14:529-544(2003).
RN [20]
RP INTERACTION WITH TAB3/MAP3K7IP3.
RX PubMed=14670075; DOI=10.1042/bj20031794;
RA Cheung P.C., Nebreda A.R., Cohen P.;
RT "TAB3, a new binding partner of the protein kinase TAK1.";
RL Biochem. J. 378:27-34(2004).
RN [21]
RP INTERACTION WITH DAB2.
RX PubMed=15894542; DOI=10.1074/jbc.m501150200;
RA Hocevar B.A., Prunier C., Howe P.H.;
RT "Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-
RT stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and
RT activation of the JNK pathway.";
RL J. Biol. Chem. 280:25920-25927(2005).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [23]
RP UBIQUITINATION, PHOSPHORYLATION AT THR-187 BY AUTOCATALYSIS, SUBUNIT, AND
RP FUNCTION.
RX PubMed=16845370; DOI=10.1038/sj.embor.7400754;
RA Thiefes A., Wolf A., Doerrie A., Grassl G.A., Matsumoto K., Autenrieth I.,
RA Bohn E., Sakurai H., Niedenthal R., Resch K., Kracht M.;
RT "The Yersinia enterocolitica effector YopP inhibits host cell signalling by
RT inactivating the protein kinase TAK1 in the IL-1 signalling pathway.";
RL EMBO Rep. 7:838-844(2006).
RN [24]
RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH TAOK1 AND TAOK2.
RX PubMed=16893890; DOI=10.1074/jbc.m603627200;
RA Huangfu W.C., Omori E., Akira S., Matsumoto K., Ninomiya-Tsuji J.;
RT "Osmotic stress activates the TAK1-JNK pathway while blocking TAK1-mediated
RT NF-kappaB activation: TAO2 regulates TAK1 pathways.";
RL J. Biol. Chem. 281:28802-28810(2006).
RN [25]
RP ACTIVITY REGULATION, INTERACTION WITH PP2A AND PPP6C, AND DEPHOSPHORYLATION
RP AT THR-187 BY PP2A AND PPP6C.
RX PubMed=17079228; DOI=10.1074/jbc.m608155200;
RA Kajino T., Ren H., Iemura S., Natsume T., Stefansson B., Brautigan D.L.,
RA Matsumoto K., Ninomiya-Tsuji J.;
RT "Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1
RT signaling pathway.";
RL J. Biol. Chem. 281:39891-39896(2006).
RN [26]
RP INTERACTION WITH RBCK1.
RX PubMed=17449468; DOI=10.1074/jbc.m701913200;
RA Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M.,
RA Chen D.Y., Zhai Z.H., Shu H.B.;
RT "RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-
RT triggered NF-kappaB activation by targeting TAB2/3 for degradation.";
RL J. Biol. Chem. 282:16776-16782(2007).
RN [27]
RP UBIQUITINATION, INTERACTION WITH CYLD, AND DEUBIQUITINATION BY CYLD.
RX PubMed=17548520; DOI=10.1084/jem.20062694;
RA Reiley W.W., Jin W., Lee A.J., Wright A., Wu X., Tewalt E.F., Leonard T.O.,
RA Norbury C.C., Fitzpatrick L., Zhang M., Sun S.C.;
RT "Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent
RT kinase Tak1 and prevents abnormal T cell responses.";
RL J. Exp. Med. 204:1475-1485(2007).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, 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 [30]
RP INTERACTION WITH TGFBR1.
RX PubMed=18758450; DOI=10.1038/ncb1780;
RA Sorrentino A., Thakur N., Grimsby S., Marcusson A., von Bulow V.,
RA Schuster N., Zhang S., Heldin C.H., Landstrom M.;
RT "The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor
RT kinase-independent manner.";
RL Nat. Cell Biol. 10:1199-1207(2008).
RN [31]
RP INTERACTION WITH VRK2.
RX PubMed=18286207; DOI=10.1371/journal.pone.0001660;
RA Blanco S., Sanz-Garcia M., Santos C.R., Lazo P.A.;
RT "Modulation of interleukin-1 transcriptional response by the interaction
RT between VRK2 and the JIP1 scaffold protein.";
RL PLoS ONE 3:E1660-E1660(2008).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, AND
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 [33]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [34]
RP INTERACTION WITH DYNC2I2.
RX PubMed=19521662; DOI=10.1007/s00018-009-0059-6;
RA Gao D., Wang R., Li B., Yang Y., Zhai Z., Chen D.Y.;
RT "WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced
RT NF-kappaB activation pathway.";
RL Cell. Mol. Life Sci. 66:2573-2584(2009).
RN [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [36]
RP INTERACTION WITH TAB2, AND PHOSPHORYLATION AT THR-187.
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 [37]
RP REVIEW ON ACTIVITY REGULATION.
RX PubMed=17496917; DOI=10.1038/sj.onc.1210413;
RA Adhikari A., Xu M., Chen Z.J.;
RT "Ubiquitin-mediated activation of TAK1 and IKK.";
RL Oncogene 26:3214-3226(2007).
RN [38]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [39]
RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=20060931; DOI=10.1016/j.biocel.2009.12.023;
RA Landstrom M.;
RT "The TAK1-TRAF6 signalling pathway.";
RL Int. J. Biochem. Cell Biol. 42:585-589(2010).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, 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 [41]
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 [42]
RP INTERACTION WITH TRIM8.
RX PubMed=22084099; DOI=10.1073/pnas.1110946108;
RA Li Q., Yan J., Mao A.P., Li C., Ran Y., Shu H.B., Wang Y.Y.;
RT "Tripartite motif 8 (TRIM8) modulates TNFalpha- and IL-1beta-triggered NF-
RT kappaB activation by targeting TAK1 for K63-linked polyubiquitination.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:19341-19346(2011).
RN [43]
RP FUNCTION, INTERACTION WITH TRIM5, AND PHOSPHORYLATION AT THR-187.
RX PubMed=21512573; DOI=10.1038/nature09976;
RA Pertel T., Hausmann S., Morger D., Zueger S., Guerra J., Lascano J.,
RA Reinhard C., Santoni F.A., Uchil P.D., Chatel L., Bisiaux A., Albert M.L.,
RA Strambio-De-Castillia C., Mothes W., Pizzato M., Gruetter M.G., Luban J.;
RT "TRIM5 is an innate immune sensor for the retrovirus capsid lattice.";
RL Nature 472:361-365(2011).
RN [44]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389 AND SER-439, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [45]
RP ACETYLATION AT THR-184; THR-187; THR-341; THR-444; THR-446; THR-448 AND
RP THR-467 (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 [46]
RP UBIQUITINATION AT LYS-72.
RX PubMed=22406003; DOI=10.1016/j.cellsig.2012.02.017;
RA Fan Y., Shi Y., Liu S., Mao R., An L., Zhao Y., Zhang H., Zhang F., Xu G.,
RA Qin J., Yang J.;
RT "Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNFalpha-
RT induced NF-kappaB activation via mediating TAK1 degradation.";
RL Cell. Signal. 24:1381-1389(2012).
RN [47]
RP ACETYLATION AT THR-184 AND THR-187 (MICROBIAL INFECTION), AND MUTAGENESIS
RP OF LYS-63.
RX PubMed=22802624; DOI=10.1073/pnas.1008203109;
RA Paquette N., Conlon J., Sweet C., Rus F., Wilson L., Pereira A.,
RA Rosadini C.V., Goutagny N., Weber A.N., Lane W.S., Shaffer S.A.,
RA Maniatis S., Fitzgerald K.A., Stuart L., Silverman N.;
RT "Serine/threonine acetylation of TGFbeta-activated kinase (TAK1) by
RT Yersinia pestis YopJ inhibits innate immune signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12710-12715(2012).
RN [48]
RP INTERACTION WITH SASH1.
RX PubMed=23776175; DOI=10.4049/jimmunol.1200583;
RA Dauphinee S.M., Clayton A., Hussainkhel A., Yang C., Park Y.J.,
RA Fuller M.E., Blonder J., Veenstra T.D., Karsan A.;
RT "SASH1 is a scaffold molecule in endothelial TLR4 signaling.";
RL J. Immunol. 191:892-901(2013).
RN [49]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-367; SER-389; SER-439 AND
RP SER-455, 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 [50]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439, AND IDENTIFICATION BY
RP 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 [51]
RP INTERACTION WITH IFIT5.
RX PubMed=26334375; DOI=10.1016/j.cellsig.2015.08.018;
RA Zheng C., Zheng Z., Zhang Z., Meng J., Liu Y., Ke X., Hu Q., Wang H.;
RT "IFIT5 positively regulates NF-kappaB signaling through synergizing the
RT recruitment of IkappaB kinase (IKK) to TGF-beta-activated kinase 1
RT (TAK1).";
RL Cell. Signal. 27:2343-2354(2015).
RN [52]
RP INVOLVEMENT IN FMD2, VARIANTS FMD2 GLN-70; GLU-100; ARG-168 AND LEU-512,
RP CHARACTERIZATION OF VARIANTS FMD2 LEU-512 AND ARG-168, SUBUNIT, AND
RP MUTAGENESIS OF PRO-512.
RX PubMed=27426733; DOI=10.1016/j.ajhg.2016.05.024;
RA Wade E.M., Daniel P.B., Jenkins Z.A., McInerney-Leo A., Leo P., Morgan T.,
RA Addor M.C., Ades L.C., Bertola D., Bohring A., Carter E., Cho T.J.,
RA Duba H.C., Fletcher E., Kim C.A., Krakow D., Morava E., Neuhann T.,
RA Superti-Furga A., Veenstra-Knol I., Wieczorek D., Wilson L.C.,
RA Hennekam R.C., Sutherland-Smith A.J., Strom T.M., Wilkie A.O., Brown M.A.,
RA Duncan E.L., Markie D.M., Robertson S.P.;
RT "Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex
RT cause frontometaphyseal dysplasia.";
RL Am. J. Hum. Genet. 99:392-406(2016).
RN [53]
RP INVOLVEMENT IN CSCF, AND VARIANTS CSCF VAL-50 DEL; CYS-110 AND ARG-241.
RX PubMed=27426734; DOI=10.1016/j.ajhg.2016.06.005;
RA Le Goff C., Rogers C., Le Goff W., Pinto G., Bonnet D., Chrabieh M.,
RA Alibeu O., Nistchke P., Munnich A., Picard C., Cormier-Daire V.;
RT "Heterozygous mutations in MAP3K7, encoding TGF-beta-activated kinase 1,
RT cause cardiospondylocarpofacial syndrome.";
RL Am. J. Hum. Genet. 99:407-413(2016).
RN [54]
RP INTERACTION WITH HHV-2 PROTEIN US2 (MICROBIAL INFECTION).
RX PubMed=28827540; DOI=10.1038/s41598-017-08856-4;
RA Lu X., Huang C., Zhang Y., Lin Y., Wang X., Li Q., Liu S., Tang J.,
RA Zhou L.;
RT "The Us2 Gene Product of herpes dimplex virus 2 modulates NF-kappaB
RT activation by targeting TAK1.";
RL Sci. Rep. 7:8396-8396(2017).
RN [55]
RP PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION).
RX PubMed=28424289; DOI=10.1128/jvi.00546-17;
RA Rui Y., Su J., Wang H., Chang J., Wang S., Zheng W., Cai Y., Wei W.,
RA Gordy J.T., Markham R., Kong W., Zhang W., Yu X.F.;
RT "Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of
RT Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68.";
RL J. Virol. 91:0-0(2017).
RN [56]
RP ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-34; LYS-158 AND LYS-209.
RX PubMed=29291351; DOI=10.1038/nm.4461;
RA Ji Y.X., Huang Z., Yang X., Wang X., Zhao L.P., Wang P.X., Zhang X.J.,
RA Alves-Bezerra M., Cai L., Zhang P., Lu Y.X., Bai L., Gao M.M., Zhao H.,
RA Tian S., Wang Y., Huang Z.X., Zhu X.Y., Zhang Y., Gong J., She Z.G., Li F.,
RA Cohen D.E., Li H.;
RT "The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic
RT steatohepatitis.";
RL Nat. Med. 24:213-223(2018).
RN [57]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND PHOSPHORYLATION AT
RP THR-184 AND THR-187.
RX PubMed=37832545; DOI=10.1016/j.molcel.2023.09.009;
RA Ma M., Dang Y., Chang B., Wang F., Xu J., Chen L., Su H., Li J., Ge B.,
RA Chen C., Liu H.;
RT "TAK1 is an essential kinase for STING trafficking.";
RL Mol. Cell 0:0-0(2023).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 31-328 IN COMPLEX WITH TAB1 AND
RP ADENOSINE, AND COFACTOR.
RX PubMed=16289117; DOI=10.1016/j.jmb.2005.09.098;
RA Brown K., Vial S.C., Dedi N., Long J.M., Dunster N.J., Cheetham G.M.T.;
RT "Structural basis for the interaction of TAK1 kinase with its activating
RT protein TAB1.";
RL J. Mol. Biol. 354:1013-1020(2005).
RN [59]
RP VARIANT GLN-410.
RX PubMed=28397838; DOI=10.1038/mp.2017.60;
RA Harripaul R., Vasli N., Mikhailov A., Rafiq M.A., Mittal K.,
RA Windpassinger C., Sheikh T.I., Noor A., Mahmood H., Downey S., Johnson M.,
RA Vleuten K., Bell L., Ilyas M., Khan F.S., Khan V., Moradi M., Ayaz M.,
RA Naeem F., Heidari A., Ahmed I., Ghadami S., Agha Z., Zeinali S., Qamar R.,
RA Mozhdehipanah H., John P., Mir A., Ansar M., French L., Ayub M.,
RA Vincent J.B.;
RT "Mapping autosomal recessive intellectual disability: combined microarray
RT and exome sequencing identifies 26 novel candidate genes in 192
RT consanguineous families.";
RL Mol. Psychiatry 23:973-984(2018).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential component
CC of the MAP kinase signal transduction pathway (PubMed:10094049,
CC PubMed:11460167, PubMed:12589052, PubMed:16845370, PubMed:16893890,
CC PubMed:21512573, PubMed:8663074, PubMed:9079627). Plays an important
CC role in the cascades of cellular responses evoked by changes in the
CC environment (PubMed:10094049, PubMed:11460167, PubMed:12589052,
CC PubMed:16845370, PubMed:16893890, PubMed:21512573, PubMed:8663074,
CC PubMed:9079627). Mediates signal transduction of TRAF6, various
CC cytokines including interleukin-1 (IL-1), transforming growth factor-
CC beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like
CC receptors (TLR), tumor necrosis factor receptor CD40 and B-cell
CC receptor (BCR) (PubMed:9079627, PubMed:16893890). Once activated, acts
CC as an upstream activator of the MKK/JNK signal transduction cascade and
CC the p38 MAPK signal transduction cascade through the phosphorylation
CC and activation of several MAP kinase kinases like MAP2K1/MEK1,
CC MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7 (PubMed:8663074,
CC PubMed:11460167). These MAP2Ks in turn activate p38 MAPKs and c-jun N-
CC terminal kinases (JNKs); both p38 MAPK and JNK pathways control the
CC transcription factors activator protein-1 (AP-1) (PubMed:8663074,
CC PubMed:11460167, PubMed:12589052). Independently of MAP2Ks and p38
CC MAPKs, acts as a key activator of NF-kappa-B by promoting activation of
CC the I-kappa-B-kinase (IKK) core complex (PubMed:8663074,
CC PubMed:12589052). Mechanistically, recruited to polyubiquitin chains of
CC RIPK2 and IKBKG/NEMO via TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3, and
CC catalyzes phosphorylation and activation of IKBKB/IKKB component of the
CC IKK complex, leading to NF-kappa-B activation (PubMed:10094049,
CC PubMed:11460167). In osmotic stress signaling, plays a major role in
CC the activation of MAPK8/JNK1, but not that of NF-kappa-B
CC (PubMed:16893890). Promotes TRIM5 capsid-specific restriction activity
CC (PubMed:21512573). Phosphorylates RIPK1 at 'Ser-321' which 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 (By similarity). Phosphorylates STING1 in
CC response to cGAMP-activation, promoting association between STEEP1 and
CC STING1 and STING1 translocation to COPII vesicles (PubMed:37832545).
CC {ECO:0000250|UniProtKB:Q62073, ECO:0000269|PubMed:10094049,
CC ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12589052,
CC ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890,
CC ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:37832545,
CC ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9079627}.
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=2.7.11.25;
CC Evidence={ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:10838074,
CC ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:37832545};
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=2.7.11.25; Evidence={ECO:0000269|PubMed:10094049,
CC ECO:0000269|PubMed:10838074, ECO:0000269|PubMed:12589052};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000305|PubMed:16289117};
CC -!- ACTIVITY REGULATION: Activated by pro-inflammatory cytokines and in
CC response to physical and chemical stresses, including osmotic stress,
CC oxidative stress, arsenic and ultraviolet light irradiation
CC (PubMed:16893890). Activated by 'Lys-63'-linked polyubiquitination and
CC by autophosphorylation (PubMed:10702308, PubMed:11460167,
CC PubMed:12242293, PubMed:29291351). Association with TAB1/MAP3K7IP1 and
CC TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas
CC PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation
CC (PubMed:11104763, PubMed:17079228, PubMed:37832545). Ceramides are also
CC able to activate MAP3K7/TAK1 (PubMed:9079627).
CC {ECO:0000269|PubMed:10702308, ECO:0000269|PubMed:11104763,
CC ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12242293,
CC ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:17079228,
CC ECO:0000269|PubMed:29291351, ECO:0000269|PubMed:37832545,
CC ECO:0000269|PubMed:9079627}.
CC -!- SUBUNIT: Can form homodimer (PubMed:27426733). Binds both upstream
CC activators and downstream substrates in multimolecular complexes.
CC Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3
CC (PubMed:10838074, PubMed:11460167, PubMed:12242293, PubMed:14670075,
CC PubMed:16289117, PubMed:19675569, PubMed:8638164). Identified in the
CC TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and
CC TAB2/MAP3K7IP2 (PubMed:11460167). Interacts with PPM1L and PPM1B/PP2CB
CC (PubMed:11104763). Interaction with PP2A and PPP6C leads to its
CC repressed activity (PubMed:17079228). Interacts with TRAF6 and
CC TAB1/MAP3K7IP1; during IL-1 signaling (PubMed:10094049,
CC PubMed:12242293). Interacts with TAOK1 and TAOK2; interaction with
CC TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-
CC kappa-B activation (PubMed:16893890). Interacts with DYNC2I2 (via WD
CC domains) (PubMed:19521662). Interacts with CYLD and RBCK1
CC (PubMed:17449468, PubMed:17548520). Interacts with TGFBR1; induces
CC MAP3K7/TAK1 activation by TRAF6 (PubMed:18758450). Interacts with
CC MAPK8IP1 and SMAD6 (By similarity). Interacts with isoform 1 of VRK2
CC (PubMed:18286207). Interacts with DAB2; the interaction is induced by
CC TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation
CC (PubMed:15894542). Interacts with TRIM5 (PubMed:21512573). Part of a
CC complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts
CC with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7
CC and enhances IKK phosphorylation (PubMed:26334375). Interacts with
CC PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with TRIM8
CC (PubMed:22084099). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7,
CC MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts
CC with SASH1 (PubMed:23776175). Interacts with RIPK1 (By similarity).
CC {ECO:0000250|UniProtKB:Q62073, ECO:0000269|PubMed:10094049,
CC ECO:0000269|PubMed:10838074, ECO:0000269|PubMed:11104763,
CC ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12242293,
CC ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:12804775,
CC ECO:0000269|PubMed:12874243, ECO:0000269|PubMed:14670075,
CC ECO:0000269|PubMed:15894542, ECO:0000269|PubMed:16289117,
CC ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890,
CC ECO:0000269|PubMed:17079228, ECO:0000269|PubMed:17449468,
CC ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:18286207,
CC ECO:0000269|PubMed:18758450, ECO:0000269|PubMed:19521662,
CC ECO:0000269|PubMed:19675569, ECO:0000269|PubMed:21512573,
CC ECO:0000269|PubMed:22084099, ECO:0000269|PubMed:23776175,
CC ECO:0000269|PubMed:26334375, ECO:0000269|PubMed:27426733,
CC ECO:0000269|PubMed:8638164}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus 2
CC protein US2; this interaction induces MAP3K7 phosphorylation and
CC subsequent activation. {ECO:0000269|PubMed:28827540}.
CC -!- INTERACTION:
CC O43318; Q16543: CDC37; NbExp=2; IntAct=EBI-358684, EBI-295634;
CC O43318; O14920: IKBKB; NbExp=6; IntAct=EBI-358684, EBI-81266;
CC O43318; O14733: MAP2K7; NbExp=3; IntAct=EBI-358684, EBI-492605;
CC O43318; Q9UQF2: MAPK8IP1; NbExp=11; IntAct=EBI-358684, EBI-78404;
CC O43318; O00743: PPP6C; NbExp=4; IntAct=EBI-358684, EBI-359751;
CC O43318; P40763: STAT3; NbExp=4; IntAct=EBI-358684, EBI-518675;
CC O43318; Q15750: TAB1; NbExp=6; IntAct=EBI-358684, EBI-358643;
CC O43318; Q9NYJ8: TAB2; NbExp=7; IntAct=EBI-358684, EBI-358708;
CC O43318; Q8N5C8: TAB3; NbExp=4; IntAct=EBI-358684, EBI-359964;
CC O43318; Q9UKE5: TNIK; NbExp=3; IntAct=EBI-358684, EBI-1051794;
CC O43318; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-358684, EBI-359276;
CC O43318; P0CG48: UBC; NbExp=4; IntAct=EBI-358684, EBI-3390054;
CC O43318; B5Z6S0: cagA; Xeno; NbExp=4; IntAct=EBI-358684, EBI-7287204;
CC O43318; P0DTC9: N; Xeno; NbExp=4; IntAct=EBI-358684, EBI-25475856;
CC O43318-2; Q16543: CDC37; NbExp=5; IntAct=EBI-358700, EBI-295634;
CC O43318-2; P07900: HSP90AA1; NbExp=5; IntAct=EBI-358700, EBI-296047;
CC O43318-2; Q15750: TAB1; NbExp=3; IntAct=EBI-358700, EBI-358643;
CC O43318-2; Q9NYJ8: TAB2; NbExp=2; IntAct=EBI-358700, EBI-358708;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12242293}. Cell
CC membrane {ECO:0000269|PubMed:12242293}; Peripheral membrane protein
CC {ECO:0000269|PubMed:12242293}; Cytoplasmic side
CC {ECO:0000269|PubMed:12242293}. Note=Although the majority of
CC MAP3K7/TAK1 is found in the cytosol, when complexed with TAB1/MAP3K7IP1
CC and TAB2/MAP3K7IP2, it is also localized at the cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1B;
CC IsoId=O43318-1; Sequence=Displayed;
CC Name=1A;
CC IsoId=O43318-2; Sequence=VSP_004886;
CC Name=1C;
CC IsoId=O43318-3; Sequence=VSP_004887, VSP_004888;
CC Name=1D;
CC IsoId=O43318-4; Sequence=VSP_004886, VSP_004887, VSP_004888;
CC -!- TISSUE SPECIFICITY: Isoform 1A is the most abundant in ovary, skeletal
CC muscle, spleen and blood mononuclear cells. Isoform 1B is highly
CC expressed in brain, kidney and small intestine. Isoform 1C is the major
CC form in prostate. Isoform 1D is the less abundant form.
CC {ECO:0000269|PubMed:11118615}.
CC -!- PTM: Association with TAB1/MAP3K7IP1 promotes autophosphorylation at
CC Ser-192 and subsequent activation. Association with TAB2/MAP3K7IP2,
CC itself associated with free unanchored Lys-63 polyubiquitin chain,
CC promotes autophosphorylation and subsequent activation of MAP3K7.
CC Dephosphorylation at Ser-192 by PPM1B/PP2CB and at Thr-187 by PP2A and
CC PPP6C leads to inactivation. {ECO:0000269|PubMed:10702308,
CC ECO:0000269|PubMed:10838074, ECO:0000269|PubMed:16845370,
CC ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:19675569,
CC ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:37832545}.
CC -!- PTM: 'Lys-48'-linked polyubiquitination at Lys-72 is induced by
CC TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-
CC linked polyubiquitination catalyzed by ITCH (By similarity). Requires
CC 'Lys-63'-linked polyubiquitination for autophosphorylation and
CC subsequent activation. 'Lys-63'-linked ubiquitination does not lead to
CC proteasomal degradation. Deubiquitinated by CYLD, a protease that
CC selectively cleaves 'Lys-63'-linked ubiquitin chains. Deubiquitinated
CC by Y.enterocolitica YopP. {ECO:0000250|UniProtKB:Q62073,
CC ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:22406003}.
CC -!- PTM: (Microbial infection) Cleaved and inactivated by the proteases 3C
CC of coxsackievirus A16 and human enterovirus D68, allowing the virus to
CC disrupt TRAF6-triggered NF-kappa-B induction.
CC {ECO:0000269|PubMed:28424289}.
CC -!- PTM: (Microbial infection) Acetylation of Thr-184 and Thr-187 by
CC Yersinia YopJ prevents phosphorylation and activation, thus blocking
CC the MAPK signaling pathway. {ECO:0000269|PubMed:22520462,
CC ECO:0000269|PubMed:22802624}.
CC -!- DISEASE: Frontometaphyseal dysplasia 2 (FMD2) [MIM:617137]: A form of
CC frontometaphyseal dysplasia, a progressive sclerosing skeletal
CC dysplasia affecting the long bones and skull. Characteristic features
CC include supraorbital hyperostosis, cranial hyperostosis, undermodeling
CC of the small bones, flared metaphyses, and digital anomalies. Extra-
CC skeletal manifestations include hearing loss, cardiac malformations,
CC and stenosis, particularly of the upper airway and urinary tract. FMD2
CC inheritance is autosomal dominant. {ECO:0000269|PubMed:27426733}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Cardiospondylocarpofacial syndrome (CSCF) [MIM:157800]: A
CC syndrome characterized by growth retardation, dysmorphic facial
CC features, brachydactyly with carpal-tarsal fusion and extensive
CC posterior cervical vertebral synostosis, cardiac septal defects with
CC valve dysplasia, and deafness with inner ear malformations. CSCF
CC transmission pattern is consistent with autosomal dominant inheritance.
CC {ECO:0000269|PubMed:27426734}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="https://atlasgeneticsoncology.org/gene/454/MAP3K7";
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DR EMBL; AB009357; BAA25026.1; -; mRNA.
DR EMBL; AB009356; BAA25025.1; -; mRNA.
DR EMBL; AB009358; BAA25027.2; -; mRNA.
DR EMBL; AF218074; AAF27652.1; -; mRNA.
DR EMBL; DQ314875; ABC40734.1; -; Genomic_DNA.
DR EMBL; AK315774; BAG38124.1; -; mRNA.
DR EMBL; AL121964; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121837; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW48525.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW48526.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW48527.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW48529.1; -; Genomic_DNA.
DR EMBL; BC017715; AAH17715.1; -; mRNA.
DR CCDS; CCDS5027.1; -. [O43318-2]
DR CCDS; CCDS5028.1; -. [O43318-1]
DR CCDS; CCDS5029.1; -. [O43318-3]
DR CCDS; CCDS5030.1; -. [O43318-4]
DR PIR; JC5955; JC5955.
DR PIR; JC5956; JC5956.
DR RefSeq; NP_003179.1; NM_003188.3. [O43318-2]
DR RefSeq; NP_663304.1; NM_145331.2. [O43318-1]
DR RefSeq; NP_663305.1; NM_145332.2. [O43318-3]
DR RefSeq; NP_663306.1; NM_145333.2. [O43318-4]
DR PDB; 2EVA; X-ray; 2.00 A; A=31-303.
DR PDB; 2YIY; X-ray; 2.49 A; A=31-303.
DR PDB; 4GS6; X-ray; 2.20 A; A=31-303.
DR PDB; 4L3P; X-ray; 2.68 A; A=31-303.
DR PDB; 4L52; X-ray; 2.54 A; A=31-303.
DR PDB; 4L53; X-ray; 2.55 A; A=31-303.
DR PDB; 4O91; X-ray; 2.39 A; A=31-303.
DR PDB; 5E7R; X-ray; 2.11 A; A=31-303.
DR PDB; 5GJD; X-ray; 2.79 A; A=31-303.
DR PDB; 5GJF; X-ray; 2.89 A; A=31-303.
DR PDB; 5GJG; X-ray; 2.61 A; A=31-303.
DR PDB; 5J7S; X-ray; 2.37 A; A=31-303.
DR PDB; 5J8I; X-ray; 2.40 A; A=31-303.
DR PDB; 5J9L; X-ray; 2.75 A; A=31-303.
DR PDB; 5JGA; X-ray; 2.00 A; A=31-303.
DR PDB; 5JGB; X-ray; 2.80 A; A=31-303.
DR PDB; 5JGD; X-ray; 3.10 A; A=31-303.
DR PDB; 5JH6; X-ray; 2.37 A; A=31-303.
DR PDB; 5JK3; X-ray; 2.37 A; A=31-303.
DR PDB; 5V5N; X-ray; 2.01 A; A=31-303.
DR PDB; 7NTH; X-ray; 1.97 A; A=31-303.
DR PDB; 7NTI; X-ray; 1.98 A; A=31-303.
DR PDB; 8GW3; X-ray; 2.05 A; A/B/C/D=15-303.
DR PDBsum; 2EVA; -.
DR PDBsum; 2YIY; -.
DR PDBsum; 4GS6; -.
DR PDBsum; 4L3P; -.
DR PDBsum; 4L52; -.
DR PDBsum; 4L53; -.
DR PDBsum; 4O91; -.
DR PDBsum; 5E7R; -.
DR PDBsum; 5GJD; -.
DR PDBsum; 5GJF; -.
DR PDBsum; 5GJG; -.
DR PDBsum; 5J7S; -.
DR PDBsum; 5J8I; -.
DR PDBsum; 5J9L; -.
DR PDBsum; 5JGA; -.
DR PDBsum; 5JGB; -.
DR PDBsum; 5JGD; -.
DR PDBsum; 5JH6; -.
DR PDBsum; 5JK3; -.
DR PDBsum; 5V5N; -.
DR PDBsum; 7NTH; -.
DR PDBsum; 7NTI; -.
DR PDBsum; 8GW3; -.
DR AlphaFoldDB; O43318; -.
DR SMR; O43318; -.
DR BioGRID; 112748; 381.
DR CORUM; O43318; -.
DR DIP; DIP-27523N; -.
DR IntAct; O43318; 176.
DR MINT; O43318; -.
DR STRING; 9606.ENSP00000358335; -.
DR BindingDB; O43318; -.
DR ChEMBL; CHEMBL5776; -.
DR DrugCentral; O43318; -.
DR GuidetoPHARMACOLOGY; 2082; -.
DR MoonDB; O43318; Predicted.
DR GlyCosmos; O43318; 2 sites, 1 glycan.
DR GlyGen; O43318; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; O43318; -.
DR MetOSite; O43318; -.
DR PhosphoSitePlus; O43318; -.
DR BioMuta; MAP3K7; -.
DR CPTAC; CPTAC-1048; -.
DR CPTAC; CPTAC-2812; -.
DR CPTAC; CPTAC-3093; -.
DR CPTAC; CPTAC-853; -.
DR CPTAC; CPTAC-854; -.
DR CPTAC; CPTAC-855; -.
DR CPTAC; CPTAC-856; -.
DR EPD; O43318; -.
DR jPOST; O43318; -.
DR MassIVE; O43318; -.
DR MaxQB; O43318; -.
DR PaxDb; 9606-ENSP00000358335; -.
DR PeptideAtlas; O43318; -.
DR ProteomicsDB; 48898; -. [O43318-1]
DR ProteomicsDB; 48899; -. [O43318-2]
DR ProteomicsDB; 48900; -. [O43318-3]
DR ProteomicsDB; 48901; -. [O43318-4]
DR Pumba; O43318; -.
DR Antibodypedia; 2078; 1472 antibodies from 45 providers.
DR DNASU; 6885; -.
DR Ensembl; ENST00000369325.7; ENSP00000358331.3; ENSG00000135341.19. [O43318-3]
DR Ensembl; ENST00000369327.7; ENSP00000358333.3; ENSG00000135341.19. [O43318-4]
DR Ensembl; ENST00000369329.8; ENSP00000358335.3; ENSG00000135341.19. [O43318-1]
DR Ensembl; ENST00000369332.7; ENSP00000358338.3; ENSG00000135341.19. [O43318-2]
DR Ensembl; ENST00000700580.1; ENSP00000515074.1; ENSG00000135341.19. [O43318-2]
DR GeneID; 6885; -.
DR KEGG; hsa:6885; -.
DR MANE-Select; ENST00000369329.8; ENSP00000358335.3; NM_145331.3; NP_663304.1.
DR UCSC; uc003pnz.3; human. [O43318-1]
DR AGR; HGNC:6859; -.
DR CTD; 6885; -.
DR DisGeNET; 6885; -.
DR GeneCards; MAP3K7; -.
DR HGNC; HGNC:6859; MAP3K7.
DR HPA; ENSG00000135341; Low tissue specificity.
DR MalaCards; MAP3K7; -.
DR MIM; 157800; phenotype.
DR MIM; 602614; gene.
DR MIM; 617137; phenotype.
DR neXtProt; NX_O43318; -.
DR OpenTargets; ENSG00000135341; -.
DR Orphanet; 3238; Cardiospondylocarpofacial syndrome.
DR Orphanet; 1826; Frontometaphyseal dysplasia.
DR PharmGKB; PA30603; -.
DR VEuPathDB; HostDB:ENSG00000135341; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000157785; -.
DR HOGENOM; CLU_000288_7_41_1; -.
DR InParanoid; O43318; -.
DR OMA; ARTQCFA; -.
DR OrthoDB; 653199at2759; -.
DR PhylomeDB; O43318; -.
DR TreeFam; TF105116; -.
DR PathwayCommons; O43318; -.
DR Reactome; R-HSA-1169091; Activation of NF-kappaB in B cells.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-202424; Downstream TCR signaling.
DR Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-HSA-4086398; Ca2+ pathway.
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-5357956; TNFR1-induced NF-kappa-B signaling pathway.
DR Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-9014325; TICAM1,TRAF6-dependent induction of TAK1 complex.
DR Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR Reactome; R-HSA-937042; IRAK2 mediated activation of TAK1 complex.
DR Reactome; R-HSA-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR Reactome; R-HSA-9645460; Alpha-protein kinase 1 signaling pathway.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR Reactome; R-HSA-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
DR SignaLink; O43318; -.
DR SIGNOR; O43318; -.
DR BioGRID-ORCS; 6885; 140 hits in 1201 CRISPR screens.
DR ChiTaRS; MAP3K7; human.
DR EvolutionaryTrace; O43318; -.
DR GeneWiki; MAP3K7; -.
DR GenomeRNAi; 6885; -.
DR Pharos; O43318; Tchem.
DR PRO; PR:O43318; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O43318; Protein.
DR Bgee; ENSG00000135341; Expressed in tendon of biceps brachii and 206 other cell types or tissues.
DR ExpressionAtlas; O43318; baseline and differential.
DR Genevisible; O43318; HS.
DR GO; GO:0140672; C:ATAC complex; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProt.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IEA:Ensembl.
DR GO; GO:0035173; F:histone kinase activity; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:1990450; F:linear polyubiquitin binding; IDA:UniProt.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004707; F:MAP kinase activity; IDA:UniProtKB.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0008349; F:MAP kinase kinase kinase kinase activity; TAS:Reactome.
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:0120283; F:protein serine/threonine kinase binding; IEA:Ensembl.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IPI:WormBase.
DR GO; GO:0097110; F:scaffold protein binding; IDA:MGI.
DR GO; GO:0001223; F:transcription coactivator binding; IEA:Ensembl.
DR GO; GO:0005114; F:type II transforming growth factor beta receptor binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IMP:UniProtKB.
DR GO; GO:0043276; P:anoikis; ISS:BHF-UCL.
DR GO; GO:0007249; P:canonical NF-kappaB signal transduction; IDA:UniProt.
DR GO; GO:1904385; P:cellular response to angiotensin; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; TAS:Reactome.
DR GO; GO:0042742; P:defense response to bacterium; IDA:UniProt.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007252; P:I-kappaB phosphorylation; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProt.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:GO_Central.
DR GO; GO:0038173; P:interleukin-17A-mediated signaling pathway; IDA:UniProt.
DR GO; GO:0038172; P:interleukin-33-mediated signaling pathway; IDA:UniProt.
DR GO; GO:0007254; P:JNK cascade; IDA:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0038066; P:p38MAPK cascade; IDA:UniProt.
DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProt.
DR GO; GO:0045787; P:positive regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0045793; P:positive regulation of cell size; IEA:Ensembl.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IMP:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; ISS:BHF-UCL.
DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IMP:UniProtKB.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; IMP:UniProtKB.
DR GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0051403; P:stress-activated MAPK cascade; IDA:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR CDD; cd14058; STKc_TAK1; 1.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR049637; MAP3K7.
DR InterPro; IPR017421; MAP3K7-like.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR46716; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 7; 1.
DR PANTHER; PTHR46716:SF1; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 7; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF038168; MAPKKK7; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00220; S_TKc; 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.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding;
KW Cell membrane; Cytoplasm; Disease variant; Host-virus interaction;
KW Isopeptide bond; Kinase; Magnesium; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1..606
FT /note="Mitogen-activated protein kinase kinase kinase 7"
FT /id="PRO_0000086252"
FT DOMAIN 36..291
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..300
FT /note="Interaction with MAPK8IP1"
FT /evidence="ECO:0000250"
FT REGION 301..338
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 354..391
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 443..493
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 303..338
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 354..382
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 156
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 42..50
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 63
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 184
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462,
FT ECO:0000269|PubMed:22802624"
FT MOD_RES 184
FT /note="Phosphothreonine; by autocatalysis; alternate"
FT /evidence="ECO:0000269|PubMed:37832545,
FT ECO:0000305|PubMed:10838074"
FT MOD_RES 187
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462,
FT ECO:0000269|PubMed:22802624"
FT MOD_RES 187
FT /note="Phosphothreonine; by autocatalysis; alternate"
FT /evidence="ECO:0000269|PubMed:10838074,
FT ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:19675569,
FT ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:37832545"
FT MOD_RES 192
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:10702308,
FT ECO:0000269|PubMed:10838074"
FT MOD_RES 341
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 367
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 389
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 439
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18088087, ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 444
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 446
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 448
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT MOD_RES 455
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 467
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:22520462"
FT CROSSLNK 72
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:22406003"
FT CROSSLNK 158
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q62073"
FT CROSSLNK 209
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q62073"
FT VAR_SEQ 404..430
FT /note="Missing (in isoform 1A and isoform 1D)"
FT /evidence="ECO:0000303|PubMed:11118615,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9480845"
FT /id="VSP_004886"
FT VAR_SEQ 509..518
FT /note="PLAPCPNSKE -> ARTSCRTGPG (in isoform 1C and isoform
FT 1D)"
FT /evidence="ECO:0000303|PubMed:11118615,
FT ECO:0000303|PubMed:9480845"
FT /id="VSP_004887"
FT VAR_SEQ 519..606
FT /note="Missing (in isoform 1C and isoform 1D)"
FT /evidence="ECO:0000303|PubMed:11118615,
FT ECO:0000303|PubMed:9480845"
FT /id="VSP_004888"
FT VARIANT 50
FT /note="Missing (in CSCF; dbSNP:rs886039236)"
FT /evidence="ECO:0000269|PubMed:27426734"
FT /id="VAR_077341"
FT VARIANT 70
FT /note="E -> Q (in FMD2; dbSNP:rs886039231)"
FT /evidence="ECO:0000269|PubMed:27426733"
FT /id="VAR_077342"
FT VARIANT 100
FT /note="V -> E (in FMD2; dbSNP:rs886039232)"
FT /evidence="ECO:0000269|PubMed:27426733"
FT /id="VAR_077343"
FT VARIANT 110
FT /note="G -> C (in CSCF; dbSNP:rs886039235)"
FT /evidence="ECO:0000269|PubMed:27426734"
FT /id="VAR_077344"
FT VARIANT 168
FT /note="G -> R (in FMD2; increases autophosphorylation; no
FT effect on MAPK signaling; no effect on NF-kappa-B
FT signaling; dbSNP:rs886039233)"
FT /evidence="ECO:0000269|PubMed:27426733"
FT /id="VAR_077345"
FT VARIANT 241
FT /note="W -> R (in CSCF; dbSNP:rs886039237)"
FT /evidence="ECO:0000269|PubMed:27426734"
FT /id="VAR_077346"
FT VARIANT 410
FT /note="R -> Q (found in a consanguineous family with
FT intellectual disability; uncertain significance;
FT dbSNP:rs201721045)"
FT /evidence="ECO:0000269|PubMed:28397838"
FT /id="VAR_080761"
FT VARIANT 512
FT /note="P -> L (in FMD2; does not affect interaction with
FT TAB2; does not affect homodimerization; increases
FT autophosphorylation; increases MAPK signaling; increases
FT NF-kappa-B signaling; dbSNP:rs886039230)"
FT /evidence="ECO:0000269|PubMed:27426733"
FT /id="VAR_077347"
FT MUTAGEN 34
FT /note="K->R: No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:29291351"
FT MUTAGEN 63
FT /note="K->W: Loss of kinase activity. Loss of
FT autophosphorylation."
FT /evidence="ECO:0000269|PubMed:12589052,
FT ECO:0000269|PubMed:22802624"
FT MUTAGEN 158
FT /note="K->R: Abolishes ubiquitination."
FT /evidence="ECO:0000269|PubMed:29291351"
FT MUTAGEN 209
FT /note="K->R: Strongly decreases ubiquitination."
FT /evidence="ECO:0000269|PubMed:29291351"
FT MUTAGEN 512
FT /note="P->R,A: Enhances autophosphorylation; Alters MAPK
FT signaling."
FT /evidence="ECO:0000269|PubMed:27426733"
FT HELIX 33..35
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 36..44
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 46..57
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 59..64
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 68..70
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 71..83
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 92..96
FT /evidence="ECO:0007829|PDB:7NTH"
FT TURN 97..100
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 101..105
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 108..111
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 112..117
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 118..123
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 127..145
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 159..161
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 162..165
FT /evidence="ECO:0007829|PDB:7NTH"
FT TURN 166..169
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 170..173
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 182..186
FT /evidence="ECO:0007829|PDB:5GJF"
FT HELIX 193..195
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 198..201
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 209..224
FT /evidence="ECO:0007829|PDB:7NTH"
FT TURN 228..231
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 236..244
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 257..266
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 271..273
FT /evidence="ECO:0007829|PDB:7NTH"
FT HELIX 277..288
FT /evidence="ECO:0007829|PDB:7NTH"
FT TURN 292..295
FT /evidence="ECO:0007829|PDB:7NTH"
FT STRAND 300..302
FT /evidence="ECO:0007829|PDB:5JGA"
SQ SEQUENCE 606 AA; 67196 MW; 3D8F8147CD174013 CRC64;
MSTASAASSS SSSSAGEMIE APSQVLNFEE IDYKEIEVEE VVGRGAFGVV CKAKWRAKDV
AIKQIESESE RKAFIVELRQ LSRVNHPNIV KLYGACLNPV CLVMEYAEGG SLYNVLHGAE
PLPYYTAAHA MSWCLQCSQG VAYLHSMQPK ALIHRDLKPP NLLLVAGGTV LKICDFGTAC
DIQTHMTNNK GSAAWMAPEV FEGSNYSEKC DVFSWGIILW EVITRRKPFD EIGGPAFRIM
WAVHNGTRPP LIKNLPKPIE SLMTRCWSKD PSQRPSMEEI VKIMTHLMRY FPGADEPLQY
PCQYSDEGQS NSATSTGSFM DIASTNTSNK SDTNMEQVPA TNDTIKRLES KLLKNQAKQQ
SESGRLSLGA SRGSSVESLP PTSEGKRMSA DMSEIEARIA ATTAYSKPKR GHRKTASFGN
ILDVPEIVIS GNGQPRRRSI QDLTVTGTEP GQVSSRSSSP SVRMITTSGP TSEKPTRSHP
WTPDDSTDTN GSDNSIPMAY LTLDHQLQPL APCPNSKESM AVFEQHCKMA QEYMKVQTEI
ALLLQRKQEL VAELDQDEKD QQNTSRLVQE HKKLLDENKS LSTYYQQCKK QLEVIRSQQQ
KRQGTS
//
