M3K8_HUMAN
ID M3K8_HUMAN Reviewed; 467 AA.
AC P41279; A8K2Q5; D3DRX1; Q14275; Q5T855; Q9HC81;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 8;
DE EC=2.7.11.25;
DE AltName: Full=Cancer Osaka thyroid oncogene;
DE AltName: Full=Proto-oncogene c-Cot;
DE AltName: Full=Serine/threonine-protein kinase cot;
DE AltName: Full=Tumor progression locus 2;
DE Short=TPL-2;
GN Name=MAP3K8; Synonyms=COT, ESTF;
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), AND ONCOGENIC VARIANT.
RC TISSUE=Hepatoma;
RX PubMed=2072910; DOI=10.1128/mcb.11.8.4088-4096.1991;
RA Miyoshi J., Higashi T., Mukai H., Ohuchi T., Kakunaga T.;
RT "Structure and transforming potential of the human cot oncogene encoding a
RT putative protein kinase.";
RL Mol. Cell. Biol. 11:4088-4096(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, AND
RP PHOSPHORYLATION.
RX PubMed=8226782; DOI=10.1016/s0021-9258(18)41587-6;
RA Aoki M., Sugimoto T., Sumida S., Hamada F., Akiyama T., Toyoshima K.;
RT "The human cot proto-oncogene encodes two protein serine/threonine kinases
RT with different transforming activities by alternative initiation of
RT translation.";
RL J. Biol. Chem. 268:22723-22732(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Bone;
RX PubMed=8479752;
RA Chan A.M., Chedid M., McGovern E.S., Popescu N.C., Miki T., Aaronson S.A.;
RT "Expression cDNA cloning of a serine kinase transforming gene.";
RL Oncogene 8:1329-1333(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Tongue;
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 [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-112.
RC TISSUE=T-cell;
RX PubMed=10896655; DOI=10.1074/jbc.m000382200;
RA Sanchez-Gongora E., Lisbona C., de Gregorio R., Ballester A., Calvo V.,
RA Perez-Jurado L., Alemany S.;
RT "COT kinase proto-oncogene expression in T cells: implication of the
RT JNK/SAPK signal transduction pathway in COT promoter activation.";
RL J. Biol. Chem. 275:31379-31386(2000).
RN [10]
RP ALTERNATIVE INITIATION, FUNCTION, SUBCELLULAR LOCATION, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=1833717;
RA Aoki M., Akiyama T., Miyoshi J., Toyoshima K.;
RT "Identification and characterization of protein products of the cot
RT oncogene with serine kinase activity.";
RL Oncogene 6:1515-1519(1991).
RN [11]
RP INTERACTION WITH NFKB1.
RX PubMed=9950430; DOI=10.1038/16946;
RA Belich M.P., Salmeron A., Johnston L.H., Ley S.C.;
RT "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein
RT NF-kappaB1 p105.";
RL Nature 397:363-368(1999).
RN [12]
RP FUNCTION.
RX PubMed=11342626; DOI=10.4049/jimmunol.166.10.6084;
RA Velasco-Sampayo A., Alemany S.;
RT "p27kip protein levels and E2F activity are targets of Cot kinase during G1
RT phase progression in T cells.";
RL J. Immunol. 166:6084-6090(2001).
RN [13]
RP INTERACTION WITH KSR2.
RX PubMed=12975377; DOI=10.1074/jbc.m306002200;
RA Channavajhala P.L., Wu L., Cuozzo J.W., Hall J.P., Liu W., Lin L.-L.,
RA Zhang Y.;
RT "Identification of a novel human kinase supporter of Ras (hKSR-2) that
RT functions as a negative regulator of Cot (Tpl2) signaling.";
RL J. Biol. Chem. 278:47089-47097(2003).
RN [14]
RP FUNCTION, AND INTERACTION WITH NFKB1.
RX PubMed=12667451; DOI=10.1016/s1097-2765(03)00070-4;
RA Waterfield M.R., Zhang M., Norman L.P., Sun S.C.;
RT "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase
RT signaling by governing the stability and function of the Tpl2 kinase.";
RL Mol. Cell 11:685-694(2003).
RN [15]
RP PHOSPHORYLATION AT THR-290, INTERACTION WITH KSR2, AND MUTAGENESIS OF
RP THR-290.
RX PubMed=15466476; DOI=10.1074/jbc.m403716200;
RA Luciano B.S., Hsu S., Channavajhala P.L., Lin L.L., Cuozzo J.W.;
RT "Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is
RT necessary but not sufficient for kinase activity.";
RL J. Biol. Chem. 279:52117-52123(2004).
RN [16]
RP FUNCTION, AND INTERACTION WITH NFKB1 AND TNIP2.
RX PubMed=15169888; DOI=10.1128/mcb.24.12.5235-5248.2004;
RA Lang V., Symons A., Watton S.J., Janzen J., Soneji Y., Beinke S.,
RA Howell S., Ley S.C.;
RT "ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is
RT essential for TPL-2 protein stability.";
RL Mol. Cell. Biol. 24:5235-5248(2004).
RN [17]
RP PHOSPHORYLATION AT THR-290.
RX PubMed=15699325; DOI=10.1073/pnas.0409856102;
RA Cho J., Tsichlis P.N.;
RT "Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and
RT Tpl2 activation and degradation by lipopolysaccharide.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:2350-2355(2005).
RN [18]
RP FUNCTION.
RX PubMed=16371247; DOI=10.1016/j.cellsig.2005.10.016;
RA Rodriguez C., Pozo M., Nieto E., Fernandez M., Alemany S.;
RT "TRAF6 and Src kinase activity regulates Cot activation by IL-1.";
RL Cell. Signal. 18:1376-1385(2006).
RN [19]
RP PHOSPHORYLATION AT THR-80; SER-400 AND SER-443.
RX PubMed=17472361; DOI=10.1021/pr0700293;
RA Black T.M., Andrews C.L., Kilili G., Ivan M., Tsichlis P.N., Vouros P.;
RT "Characterization of phosphorylation sites on Tpl2 using IMAC enrichment
RT and a linear ion trap mass spectrometer.";
RL J. Proteome Res. 6:2269-2276(2007).
RN [20]
RP FUNCTION, AND INDUCTION.
RX PubMed=19001140; DOI=10.1084/jem.20081461;
RA Watford W.T., Hissong B.D., Durant L.R., Yamane H., Muul L.M., Kanno Y.,
RA Tato C.M., Ramos H.L., Berger A.E., Mielke L., Pesu M., Solomon B.,
RA Frucht D.M., Paul W.E., Sher A., Jankovic D., Tsichlis P.N., O'Shea J.J.;
RT "Tpl2 kinase regulates T cell interferon-gamma production and host
RT resistance to Toxoplasma gondii.";
RL J. Exp. Med. 205:2803-2812(2008).
RN [21]
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 [22]
RP RETRACTED PAPER.
RX PubMed=19754427; DOI=10.1042/bj20091271;
RA Handoyo H., Stafford M.J., McManus E., Baltzis D., Peggie M., Cohen P.;
RT "IRAK1-independent pathways required for the interleukin-1-stimulated
RT activation of the Tpl2 catalytic subunit and its dissociation from ABIN2.";
RL Biochem. J. 424:109-118(2009).
RN [23]
RP RETRACTION NOTICE OF PUBMED:19754427.
RX PubMed=24325551; DOI=10.1042/bj4570227;
RA Stafford M.J., McManus E., Baltzis D., Peggie M., Cohen P.;
RT "Retraction. IRAK1-independent pathways required for the interleukin-1-
RT stimulated activation of the Tpl2 catalytic subunit and its dissociation
RT from ABIN2.";
RL Biochem. J. 457:227-227(2014).
RN [24]
RP FUNCTION, AND INDUCTION.
RX PubMed=19808894; DOI=10.2337/db09-0470;
RA Jager J., Gremeaux T., Gonzalez T., Bonnafous S., Debard C., Laville M.,
RA Vidal H., Tran A., Gual P., Le Marchand-Brustel Y., Cormont M., Tanti J.F.;
RT "Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate
RT interleukin-1beta and tumor necrosis factor-{alpha} effects on
RT extracellular signal-regulated kinase activation and lipolysis.";
RL Diabetes 59:61-70(2010).
RN [25]
RP PHOSPHORYLATION AT SER-400.
RX PubMed=22988300; DOI=10.1128/mcb.01065-12;
RA Roget K., Ben-Addi A., Mambole-Dema A., Gantke T., Yang H.T., Janzen J.,
RA Morrice N., Abbott D., Ley S.C.;
RT "IkappaB kinase 2 regulates TPL-2 activation of extracellular signal-
RT regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400.";
RL Mol. Cell. Biol. 32:4684-4690(2012).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, AND IDENTIFICATION BY
RP 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 [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, 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).
CC -!- FUNCTION: Required for lipopolysaccharide (LPS)-induced, TLR4-mediated
CC activation of the MAPK/ERK pathway in macrophages, thus being critical
CC for production of the pro-inflammatory cytokine TNF-alpha (TNF) during
CC immune responses. Involved in the regulation of T-helper cell
CC differentiation and IFNG expression in T-cells. Involved in mediating
CC host resistance to bacterial infection through negative regulation of
CC type I interferon (IFN) production. In vitro, activates MAPK/ERK
CC pathway in response to IL1 in an IRAK1-independent manner, leading to
CC up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals
CC that activate ERK in B-cells and macrophages, and thus may play a role
CC in the regulation of immunoglobulin production. May also play a role in
CC the transduction of TNF signals that activate JNK and NF-kappa-B in
CC some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-
CC dependent manner in response to IL1B and TNF, but not insulin, leading
CC to induction of lipolysis. Plays a role in the cell cycle. Isoform 1
CC shows some transforming activity, although it is much weaker than that
CC of the activated oncogenic variant. {ECO:0000269|PubMed:11342626,
CC ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:15169888,
CC ECO:0000269|PubMed:16371247, ECO:0000269|PubMed:1833717,
CC ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19808894}.
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 -!- 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;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- SUBUNIT: Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts
CC with NFKB1; the interaction increases the stability of MAP3K8 but
CC inhibits its MEK phosphorylation activity, whereas loss of interaction
CC following LPS stimulation leads to its degradation. Interacts with CD40
CC and TRAF6; the interaction is required for ERK activation. Interacts
CC with KSR2; the interaction inhibits ERK and NF-kappa-B activation.
CC {ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:12975377,
CC ECO:0000269|PubMed:15169888, ECO:0000269|PubMed:15466476,
CC ECO:0000269|PubMed:9950430}.
CC -!- INTERACTION:
CC P41279; P08238: HSP90AB1; NbExp=2; IntAct=EBI-354900, EBI-352572;
CC P41279; P19838: NFKB1; NbExp=14; IntAct=EBI-354900, EBI-300010;
CC P41279; Q00653: NFKB2; NbExp=2; IntAct=EBI-354900, EBI-307326;
CC P41279; Q13526: PIN1; NbExp=8; IntAct=EBI-354900, EBI-714158;
CC P41279; Q8NFZ5: TNIP2; NbExp=10; IntAct=EBI-354900, EBI-359372;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:1833717,
CC ECO:0000269|PubMed:8226782}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=1; Synonyms=58 kDa;
CC IsoId=P41279-1; Sequence=Displayed;
CC Name=2; Synonyms=52 kDa;
CC IsoId=P41279-2; Sequence=VSP_018843;
CC -!- TISSUE SPECIFICITY: Expressed in several normal tissues and human
CC tumor-derived cell lines.
CC -!- DEVELOPMENTAL STAGE: Isoform 1 is activated specifically during the S
CC and G2/M phases of the cell cycle.
CC -!- INDUCTION: Up-regulated by IL12 in T-lymphocytes. Up-regulated in
CC subcutaneous adipose tissue of obese individuals.
CC {ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19808894}.
CC -!- PTM: Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1
CC undergoes phosphorylation mainly on Ser residues, and isoform 2 on both
CC Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the
CC phosphorylation is necessary but not sufficient for full kinase
CC activity in vitro and for the dissociation of isoform 1 from NFKB1,
CC leading to its degradation (PubMed:15466476, PubMed:15699325).
CC Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for
CC LPS-stimulated activation of the MAPK/ERK pathway in macrophages
CC (PubMed:17472361, PubMed:22988300). {ECO:0000269|PubMed:15466476,
CC ECO:0000269|PubMed:15699325, ECO:0000269|PubMed:17472361,
CC ECO:0000269|PubMed:1833717, ECO:0000269|PubMed:22988300,
CC ECO:0000269|PubMed:8226782}.
CC -!- MISCELLANEOUS: Can be converted to an oncogenic protein by proviral
CC activation, leading to a C-terminally truncated protein with
CC transforming activity.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: A paper describing a role for this protein in IRAK1-
CC independent activation of the MAPK/ERK pathway in response to IL1 has
CC been retracted, because some of the experimental data could not be
CC reproduced. {ECO:0000305|PubMed:19754427, ECO:0000305|PubMed:24325551}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/map3k8/";
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DR EMBL; D14497; BAA03387.1; -; mRNA.
DR EMBL; Z14138; CAA78512.1; -; mRNA.
DR EMBL; AK290320; BAF83009.1; -; mRNA.
DR EMBL; AY309013; AAP45053.1; -; Genomic_DNA.
DR EMBL; AL161651; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471072; EAW86004.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86005.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86006.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86007.1; -; Genomic_DNA.
DR EMBL; BC104833; AAI04834.1; -; mRNA.
DR EMBL; BC113566; AAI13567.1; -; mRNA.
DR EMBL; AF133211; AAG13454.1; -; Genomic_DNA.
DR CCDS; CCDS7166.1; -. [P41279-1]
DR PIR; A48713; A48713.
DR RefSeq; NP_001231063.1; NM_001244134.1. [P41279-1]
DR RefSeq; NP_001307890.1; NM_001320961.1. [P41279-1]
DR RefSeq; NP_005195.2; NM_005204.3. [P41279-1]
DR RefSeq; XP_016871196.1; XM_017015707.1.
DR RefSeq; XP_016871197.1; XM_017015708.1. [P41279-1]
DR RefSeq; XP_016871198.1; XM_017015709.1. [P41279-1]
DR RefSeq; XP_016871199.1; XM_017015710.1. [P41279-1]
DR PDB; 4Y83; X-ray; 2.89 A; A/B/C=66-395.
DR PDB; 4Y85; X-ray; 2.33 A; A/B/C=66-395.
DR PDB; 5IU2; X-ray; 2.70 A; A/B=66-395.
DR PDBsum; 4Y83; -.
DR PDBsum; 4Y85; -.
DR PDBsum; 5IU2; -.
DR AlphaFoldDB; P41279; -.
DR SMR; P41279; -.
DR BioGRID; 107719; 27.
DR CORUM; P41279; -.
DR DIP; DIP-27534N; -.
DR IntAct; P41279; 14.
DR MINT; P41279; -.
DR STRING; 9606.ENSP00000263056; -.
DR BindingDB; P41279; -.
DR ChEMBL; CHEMBL4899; -.
DR GuidetoPHARMACOLOGY; 2083; -.
DR iPTMnet; P41279; -.
DR PhosphoSitePlus; P41279; -.
DR BioMuta; MAP3K8; -.
DR DMDM; 50403742; -.
DR CPTAC; CPTAC-858; -.
DR CPTAC; CPTAC-859; -.
DR EPD; P41279; -.
DR jPOST; P41279; -.
DR MassIVE; P41279; -.
DR MaxQB; P41279; -.
DR PaxDb; P41279; -.
DR PeptideAtlas; P41279; -.
DR PRIDE; P41279; -.
DR ProteomicsDB; 55458; -. [P41279-1]
DR ProteomicsDB; 55459; -. [P41279-2]
DR Antibodypedia; 2836; 621 antibodies from 37 providers.
DR DNASU; 1326; -.
DR Ensembl; ENST00000263056.6; ENSP00000263056.1; ENSG00000107968.10. [P41279-1]
DR Ensembl; ENST00000375321.1; ENSP00000364470.1; ENSG00000107968.10. [P41279-1]
DR Ensembl; ENST00000542547.5; ENSP00000443610.1; ENSG00000107968.10. [P41279-1]
DR GeneID; 1326; -.
DR KEGG; hsa:1326; -.
DR MANE-Select; ENST00000263056.6; ENSP00000263056.1; NM_005204.4; NP_005195.2.
DR UCSC; uc001ivi.3; human. [P41279-1]
DR CTD; 1326; -.
DR DisGeNET; 1326; -.
DR GeneCards; MAP3K8; -.
DR HGNC; HGNC:6860; MAP3K8.
DR HPA; ENSG00000107968; Tissue enriched (bone).
DR MalaCards; MAP3K8; -.
DR MIM; 191195; gene.
DR neXtProt; NX_P41279; -.
DR OpenTargets; ENSG00000107968; -.
DR PharmGKB; PA30606; -.
DR VEuPathDB; HostDB:ENSG00000107968; -.
DR eggNOG; KOG0201; Eukaryota.
DR GeneTree; ENSGT00940000158806; -.
DR HOGENOM; CLU_047137_0_0_1; -.
DR InParanoid; P41279; -.
DR OMA; FPWRLTY; -.
DR PhylomeDB; P41279; -.
DR TreeFam; TF105117; -.
DR PathwayCommons; P41279; -.
DR Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-HSA-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR SignaLink; P41279; -.
DR SIGNOR; P41279; -.
DR BioGRID-ORCS; 1326; 14 hits in 1116 CRISPR screens.
DR ChiTaRS; MAP3K8; human.
DR GeneWiki; MAP3K8; -.
DR GenomeRNAi; 1326; -.
DR Pharos; P41279; Tchem.
DR PRO; PR:P41279; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P41279; protein.
DR Bgee; ENSG00000107968; Expressed in mucosa of stomach and 159 other tissues.
DR ExpressionAtlas; P41279; baseline and differential.
DR Genevisible; P41279; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR017424; MAPKKK8.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038171; MAPKKK8; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative initiation; ATP-binding; Cell cycle; Cytoplasm;
KW Immunity; Kinase; Magnesium; Metal-binding; Nucleotide-binding;
KW Phosphoprotein; Proto-oncogene; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..467
FT /note="Mitogen-activated protein kinase kinase kinase 8"
FT /id="PRO_0000024350"
FT DOMAIN 138..388
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ACT_SITE 253
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 144..152
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 167
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 80
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:17472361"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 290
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:15466476,
FT ECO:0000269|PubMed:15699325"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:17472361,
FT ECO:0000269|PubMed:22988300"
FT MOD_RES 443
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:17472361"
FT VAR_SEQ 1..29
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8226782"
FT /id="VSP_018843"
FT VARIANT 214
FT /note="S -> F (in dbSNP:rs3087944)"
FT /id="VAR_051638"
FT VARIANT 398..415
FT /note="CQSLDSALLERKRLLSRK -> GHQVIHEGSSTNDPNNSC (in
FT oncogenic form)"
FT /id="VAR_006198"
FT VARIANT 416..467
FT /note="Missing (in oncogenic form)"
FT /id="VAR_006199"
FT MUTAGEN 290
FT /note="T->A: Loss of MEK phosphorylation activity and
FT almost abolished autophosphorylation activity. Loss of IL1-
FT stimulated MEK phosphorylation activity but not of IL1-
FT stimulated autophosphorylation activity. No effect on KSR2
FT binding."
FT /evidence="ECO:0000269|PubMed:15466476"
FT MUTAGEN 290
FT /note="T->D: Impaired MEK phosphorylation and
FT autophosphorylation activities. No effect on KSR2 binding."
FT /evidence="ECO:0000269|PubMed:15466476"
FT MUTAGEN 290
FT /note="T->E: Loss of MEK phosphorylation activity and
FT almost abolished autophosphorylation activity. No effect on
FT KSR2 binding."
FT /evidence="ECO:0000269|PubMed:15466476"
FT CONFLICT 399
FT /note="Q -> T (in Ref. 1; BAA03387 and 2; no nucleotide
FT entry)"
FT /evidence="ECO:0000305"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 81..92
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 106..109
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 117..119
FT /evidence="ECO:0007829|PDB:4Y83"
FT TURN 124..126
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 135..137
FT /evidence="ECO:0007829|PDB:4Y83"
FT STRAND 138..145
FT /evidence="ECO:0007829|PDB:4Y83"
FT STRAND 148..157
FT /evidence="ECO:0007829|PDB:4Y85"
FT TURN 158..160
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 163..170
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 171..173
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 177..184
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 193..199
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 202..207
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 215..222
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 227..246
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 256..258
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 259..261
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 266..268
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 278..282
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 296..300
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 307..322
FT /evidence="ECO:0007829|PDB:4Y85"
FT TURN 326..330
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 340..346
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 350..352
FT /evidence="ECO:0007829|PDB:4Y85"
FT STRAND 355..357
FT /evidence="ECO:0007829|PDB:5IU2"
FT HELIX 359..368
FT /evidence="ECO:0007829|PDB:4Y85"
FT TURN 373..375
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 379..382
FT /evidence="ECO:0007829|PDB:4Y85"
FT HELIX 386..388
FT /evidence="ECO:0007829|PDB:4Y85"
SQ SEQUENCE 467 AA; 52925 MW; 7728969EA3E4E8EC CRC64;
MEYMSTGSDN KEEIDLLIKH LNVSDVIDIM ENLYASEEPA VYEPSLMTMC QDSNQNDERS
KSLLLSGQEV PWLSSVRYGT VEDLLAFANH ISNTAKHFYG QRPQESGILL NMVITPQNGR
YQIDSDVLLI PWKLTYRNIG SDFIPRGAFG KVYLAQDIKT KKRMACKLIP VDQFKPSDVE
IQACFRHENI AELYGAVLWG ETVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG
LDFLHSKKVI HHDIKPSNIV FMSTKAVLVD FGLSVQMTED VYFPKDLRGT EIYMSPEVIL
CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL EDIADDCSPG
MRELIEASLE RNPNHRPRAA DLLKHEALNP PREDQPRCQS LDSALLERKR LLSRKELELP
ENIADSSCTG STEESEMLKR QRSLYIDLGA LAGYFNLVRG PPTLEYG
