MP2K4_HUMAN
ID MP2K4_HUMAN Reviewed; 399 AA.
AC P45985; B2R7N7; B3KYB2; D3DTS5; Q5U0B8; Q6FHX4; Q6P9H2; Q6PIE6;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4;
DE Short=MAP kinase kinase 4;
DE Short=MAPKK 4;
DE EC=2.7.12.2;
DE AltName: Full=JNK-activating kinase 1;
DE AltName: Full=MAPK/ERK kinase 4;
DE Short=MEK 4;
DE AltName: Full=SAPK/ERK kinase 1;
DE Short=SEK1;
DE AltName: Full=Stress-activated protein kinase kinase 1;
DE Short=SAPK kinase 1;
DE Short=SAPKK-1;
DE Short=SAPKK1;
DE AltName: Full=c-Jun N-terminal kinase kinase 1;
DE Short=JNKK;
GN Name=MAP2K4; Synonyms=JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1;
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).
RC TISSUE=Brain;
RX PubMed=7839144; DOI=10.1126/science.7839144;
RA Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J., Ulevitch R.J.,
RA Davis R.J.;
RT "Independent human MAP-kinase signal transduction pathways defined by MEK
RT and MKK isoforms.";
RL Science 267:682-685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=7716521; DOI=10.1126/science.7716521;
RA Lin A., Minden A., Martinetto H., Claret F.-X., Lange-Carter C.,
RA Mercurio F., Johnson G.L., Karin M.;
RT "Identification of a dual specificity kinase that activates the Jun kinases
RT and p38-Mpk2.";
RL Science 268:286-290(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9622070;
RA Su G.H., Hilgers W., Shekher M.C., Tang D.J., Yeo C.J., Hruban R.H.,
RA Kern S.E.;
RT "Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as
RT a genetically targeted tumor suppressor gene.";
RL Cancer Res. 58:2339-2342(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Thalamus;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-16.
RC TISSUE=Brain, and Testis;
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 [11]
RP PHOSPHORYLATION AT THR-261, ACTIVITY REGULATION, AND INTERACTION WITH
RP MAP3K11/MLK3.
RX PubMed=9003778; DOI=10.1002/j.1460-2075.1996.tb01094.x;
RA Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R.,
RA Lassam N.J.;
RT "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6.";
RL EMBO J. 15:7026-7035(1996).
RN [12]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/bj3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family members
RT to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [13]
RP INTERACTION WITH ARRB2.
RX PubMed=11090355; DOI=10.1126/science.290.5496.1574;
RA McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T.,
RA Davis R.J., Lefkowitz R.J.;
RT "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of
RT JNK3.";
RL Science 290:1574-1577(2000).
RN [14]
RP INTERACTION WITH MAPK8IP3/JIP3.
RX PubMed=12189133; DOI=10.1074/jbc.m202004200;
RA Matsuura H., Nishitoh H., Takeda K., Matsuzawa A., Amagasa T., Ito M.,
RA Yoshioka K., Ichijo H.;
RT "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK
RT signaling pathway. A new mode of regulation of the MAP kinase cascade.";
RL J. Biol. Chem. 277:40703-40709(2002).
RN [15]
RP DOMAIN, AND INTERACTION WITH MAPK8/JNK1; MAPK9/JNK2; MAPK10/JNK3; MAPK11
RP AND MAPK14.
RX PubMed=12788955; DOI=10.1074/jbc.m304229200;
RA Ho D.T., Bardwell A.J., Abdollahi M., Bardwell L.;
RT "A docking site in MKK4 mediates high affinity binding to JNK MAPKs and
RT competes with similar docking sites in JNK substrates.";
RL J. Biol. Chem. 278:32662-32672(2003).
RN [16]
RP DOMAIN.
RX PubMed=15866172; DOI=10.1016/j.molcel.2005.04.001;
RA Takekawa M., Tatebayashi K., Saito H.;
RT "Conserved docking site is essential for activation of mammalian MAP kinase
RT kinases by specific MAP kinase kinase kinases.";
RL Mol. Cell 18:295-306(2005).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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 [19]
RP INTERACTION WITH ARRB1 AND ARRB2.
RX PubMed=19782076; DOI=10.1016/j.febslet.2009.09.035;
RA Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C.,
RA Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.;
RT "A scanning peptide array approach uncovers association sites within the
RT JNK/beta arrestin signalling complex.";
RL FEBS Lett. 583:3310-3316(2009).
RN [20]
RP REVIEW ON ACTIVITY REGULATION.
RX PubMed=17496909; DOI=10.1038/sj.onc.1210392;
RA Raman M., Chen W., Cobb M.H.;
RT "Differential regulation and properties of MAPKs.";
RL Oncogene 26:3100-3112(2007).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, AND IDENTIFICATION BY
RP 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 [22]
RP REVIEW ON FUNCTION.
RX PubMed=20801953; DOI=10.1093/jb/mvq098;
RA Asaoka Y., Nishina H.;
RT "Diverse physiological functions of MKK4 and MKK7 during early
RT embryogenesis.";
RL J. Biochem. 148:393-401(2010).
RN [23]
RP IDENTIFICATION BY 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 [24]
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 [25]
RP REVIEW ON REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21333379; DOI=10.1016/j.ejcb.2010.11.008;
RA Haeusgen W., Herdegen T., Waetzig V.;
RT "The bottleneck of JNK signaling: molecular and functional characteristics
RT of MKK4 and MKK7.";
RL Eur. J. Cell Biol. 90:536-544(2011).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, 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 [27]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-58, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Colon carcinoma;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 80-399.
RX PubMed=20732303; DOI=10.1016/j.bbrc.2010.08.071;
RA Matsumoto T., Kinoshita T., Kirii Y., Yokota K., Hamada K., Tada T.;
RT "Crystal structures of MKK4 kinase domain reveal that substrate peptide
RT binds to an allosteric site and induces an auto-inhibition state.";
RL Biochem. Biophys. Res. Commun. 400:369-373(2010).
RN [29]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-142; TRP-154; ILE-234; ASN-251 AND
RP THR-279.
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: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. Essential
CC component of the stress-activated protein kinase/c-Jun N-terminal
CC kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the
CC only known kinase to directly activate the stress-activated protein
CC kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3.
CC MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation,
CC but they differ in their preference for the phosphorylation site in the
CC Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the
CC Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of
CC the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK
CC activation at least in response to pro-inflammatory cytokines, while
CC other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which
CC synergistically phosphorylate JNKs. MAP2K4 is required for maintaining
CC peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also
CC involved in mitochondrial death signaling pathway, including the
CC release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7
CC exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38
CC MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. {ECO:0000269|PubMed:7716521}.
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=2.7.12.2;
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=2.7.12.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC -!- ACTIVITY REGULATION: Activated in response to a variety of cellular
CC stresses, including UV and gamma-irradiation, heat shock,
CC hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory
CC cytokines. Also activated by developmental cues. MAP2K4/MKK4 is
CC activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
CC {ECO:0000269|PubMed:9003778}.
CC -!- SUBUNIT: Interacts with SPAG9 (By similarity). Interacts (via its D
CC domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11
CC and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like
CC MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and
CC MAPK8IP3/JIP3. {ECO:0000250, ECO:0000269|PubMed:11090355,
CC ECO:0000269|PubMed:12189133, ECO:0000269|PubMed:12788955,
CC ECO:0000269|PubMed:19782076, ECO:0000269|PubMed:9003778}.
CC -!- INTERACTION:
CC P45985; Q13233: MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776;
CC P45985; P45983: MAPK8; NbExp=2; IntAct=EBI-447868, EBI-286483;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P45985-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P45985-2; Sequence=VSP_038838;
CC -!- TISSUE SPECIFICITY: Abundant expression is seen in the skeletal muscle.
CC It is also widely expressed in other tissues.
CC -!- DOMAIN: The DVD domain (residues 364-387) contains a conserved docking
CC site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD
CC sites bind to their specific upstream MAP kinase kinase kinases
CC (MAP3Ks) and are essential for activation.
CC -!- DOMAIN: The D domain (residues 34-52) contains a conserved docking site
CC and is required for the binding to MAPK substrates.
CC -!- PTM: Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase
CC kinase kinases (MAP3Ks). {ECO:0000269|PubMed:9003778}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/map2k4/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAP2K4ID244ch17p12.html";
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DR EMBL; L36870; AAC41719.1; -; mRNA.
DR EMBL; U17743; AAC50127.1; -; mRNA.
DR EMBL; AF070090; AAC24130.1; -; Genomic_DNA.
DR EMBL; AF070080; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070081; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070082; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070083; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070084; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070085; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070086; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070087; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070088; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070089; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; CR536564; CAG38801.1; -; mRNA.
DR EMBL; BT019676; AAV38482.1; -; mRNA.
DR EMBL; AK131544; BAG54774.1; -; mRNA.
DR EMBL; AK313053; BAG35884.1; -; mRNA.
DR EMBL; DQ015703; AAY22176.1; -; Genomic_DNA.
DR EMBL; AC005244; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005410; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471108; EAW89975.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89974.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89976.1; -; Genomic_DNA.
DR EMBL; BC036032; AAH36032.1; -; mRNA.
DR EMBL; BC060764; AAH60764.1; -; mRNA.
DR CCDS; CCDS11162.1; -. [P45985-1]
DR CCDS; CCDS62095.1; -. [P45985-2]
DR PIR; I38901; I38901.
DR RefSeq; NP_001268364.1; NM_001281435.1. [P45985-2]
DR RefSeq; NP_003001.1; NM_003010.3. [P45985-1]
DR PDB; 3ALN; X-ray; 2.30 A; A/B/C=80-399.
DR PDB; 3ALO; X-ray; 2.60 A; A=80-399.
DR PDB; 3VUT; X-ray; 3.50 A; A/B=80-399.
DR PDBsum; 3ALN; -.
DR PDBsum; 3ALO; -.
DR PDBsum; 3VUT; -.
DR AlphaFoldDB; P45985; -.
DR SMR; P45985; -.
DR BioGRID; 112315; 54.
DR CORUM; P45985; -.
DR IntAct; P45985; 22.
DR MINT; P45985; -.
DR STRING; 9606.ENSP00000410402; -.
DR BindingDB; P45985; -.
DR ChEMBL; CHEMBL2897; -.
DR DrugCentral; P45985; -.
DR GuidetoPHARMACOLOGY; 2065; -.
DR GlyGen; P45985; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; P45985; -.
DR PhosphoSitePlus; P45985; -.
DR BioMuta; MAP2K4; -.
DR DMDM; 1170596; -.
DR CPTAC; CPTAC-816; -.
DR CPTAC; CPTAC-817; -.
DR EPD; P45985; -.
DR jPOST; P45985; -.
DR MassIVE; P45985; -.
DR MaxQB; P45985; -.
DR PaxDb; P45985; -.
DR PeptideAtlas; P45985; -.
DR PRIDE; P45985; -.
DR ProteomicsDB; 55703; -. [P45985-1]
DR ProteomicsDB; 55704; -. [P45985-2]
DR Antibodypedia; 3571; 1436 antibodies from 42 providers.
DR DNASU; 6416; -.
DR Ensembl; ENST00000353533.10; ENSP00000262445.5; ENSG00000065559.15. [P45985-1]
DR Ensembl; ENST00000415385.7; ENSP00000410402.3; ENSG00000065559.15. [P45985-2]
DR GeneID; 6416; -.
DR KEGG; hsa:6416; -.
DR MANE-Select; ENST00000353533.10; ENSP00000262445.5; NM_003010.4; NP_003001.1.
DR UCSC; uc002gnj.5; human. [P45985-1]
DR CTD; 6416; -.
DR DisGeNET; 6416; -.
DR GeneCards; MAP2K4; -.
DR HGNC; HGNC:6844; MAP2K4.
DR HPA; ENSG00000065559; Low tissue specificity.
DR MIM; 601335; gene.
DR neXtProt; NX_P45985; -.
DR OpenTargets; ENSG00000065559; -.
DR PharmGKB; PA30589; -.
DR VEuPathDB; HostDB:ENSG00000065559; -.
DR eggNOG; KOG1006; Eukaryota.
DR GeneTree; ENSGT00940000154744; -.
DR HOGENOM; CLU_000288_63_23_1; -.
DR InParanoid; P45985; -.
DR OMA; REVHIMT; -.
DR OrthoDB; 688282at2759; -.
DR PhylomeDB; P45985; -.
DR TreeFam; TF350701; -.
DR BRENDA; 2.7.12.2; 2681.
DR PathwayCommons; P45985; -.
DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-HSA-2871796; FCERI mediated MAPK activation.
DR Reactome; R-HSA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-HSA-5210891; Uptake and function of anthrax toxins.
DR Reactome; R-HSA-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR SABIO-RK; P45985; -.
DR SignaLink; P45985; -.
DR SIGNOR; P45985; -.
DR BioGRID-ORCS; 6416; 53 hits in 1118 CRISPR screens.
DR ChiTaRS; MAP2K4; human.
DR EvolutionaryTrace; P45985; -.
DR GeneWiki; MAP2K4; -.
DR GenomeRNAi; 6416; -.
DR Pharos; P45985; Tchem.
DR PRO; PR:P45985; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; P45985; protein.
DR Bgee; ENSG00000065559; Expressed in lateral nuclear group of thalamus and 202 other tissues.
DR ExpressionAtlas; P45985; baseline and differential.
DR Genevisible; P45985; HS.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0032839; C:dendrite cytoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008545; F:JUN kinase kinase activity; IBA:GO_Central.
DR GO; GO:0004708; F:MAP kinase kinase activity; IBA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0061049; P:cell growth involved in cardiac muscle cell development; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:2000672; P:negative regulation of motor neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0045740; P:positive regulation of DNA replication; IEA:Ensembl.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0009611; P:response to wounding; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR DisProt; DP01400; -.
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 Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 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 Cytoplasm; Kinase; Methylation; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Stress response; Transferase; Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..399
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 4"
FT /id="PRO_0000086381"
FT DOMAIN 102..367
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..40
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 37..52
FT /note="D domain"
FT REGION 364..387
FT /note="DVD domain"
FT ACT_SITE 229
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 108..116
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 131
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 45..46
FT /note="Cleavage; by anthrax lethal factor"
FT SITE 58..59
FT /note="Cleavage; by anthrax lethal factor"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 58
FT /note="Asymmetric dimethylarginine; alternate"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 58
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 90
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 257
FT /note="Phosphoserine; by MAP3K"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 261
FT /note="Phosphothreonine; by MAP3K"
FT /evidence="ECO:0000269|PubMed:9003778"
FT VAR_SEQ 39
FT /note="G -> GFQINFCEKAQS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_038838"
FT VARIANT 16
FT /note="S -> R (in dbSNP:rs17855590)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_062963"
FT VARIANT 142
FT /note="Q -> L (in a lung squamous cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040818"
FT VARIANT 154
FT /note="R -> W (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs1567657403)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040819"
FT VARIANT 234
FT /note="N -> I (in an ovarian serous carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040820"
FT VARIANT 251
FT /note="S -> N (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040821"
FT VARIANT 279
FT /note="A -> T (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs753665559)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040822"
FT CONFLICT 118
FT /note="K -> R (in Ref. 4; CAG38801)"
FT /evidence="ECO:0000305"
FT CONFLICT 179
FT /note="E -> G (in Ref. 6; BAG35884)"
FT /evidence="ECO:0000305"
FT CONFLICT 356
FT /note="P -> L (in Ref. 10; AAH60764)"
FT /evidence="ECO:0000305"
FT STRAND 81..83
FT /evidence="ECO:0007829|PDB:3VUT"
FT STRAND 85..88
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 93..95
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 101..103
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 107..110
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 112..121
FT /evidence="ECO:0007829|PDB:3ALN"
FT TURN 122..124
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 127..134
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 139..153
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 164..169
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 171..178
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 185..194
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 202..223
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 232..234
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 235..237
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 249..251
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 255..259
FT /evidence="ECO:0007829|PDB:3VUT"
FT STRAND 267..270
FT /evidence="ECO:0007829|PDB:3ALO"
FT HELIX 272..274
FT /evidence="ECO:0007829|PDB:3ALO"
FT HELIX 287..302
FT /evidence="ECO:0007829|PDB:3ALN"
FT STRAND 312..314
FT /evidence="ECO:0007829|PDB:3ALO"
FT STRAND 316..321
FT /evidence="ECO:0007829|PDB:3ALO"
FT HELIX 338..347
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 352..354
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 358..361
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 365..372
FT /evidence="ECO:0007829|PDB:3ALN"
FT HELIX 377..387
FT /evidence="ECO:0007829|PDB:3ALN"
SQ SEQUENCE 399 AA; 44288 MW; A472537F2F26770B CRC64;
MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN PPFKSTARFT
LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE DLKDLGEIGR GAYGSVNKMV
HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD VVMRSSDCPY IVQFYGALFR EGDCWICMEL
MSTSFDKFYK YVYSVLDDVI PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS
GNIKLCDFGI SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL
ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK DESKRPKYKE
LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD
