ID M4K4_HUMAN Reviewed; 1239 AA.
AC O95819; E7ESS2; O75172; Q9NST7;
DT 28-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 28-MAR-2003, sequence version 2.
DT 27-MAR-2024, entry version 219.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 4;
DE EC=2.7.11.1;
DE AltName: Full=HPK/GCK-like kinase HGK;
DE AltName: Full=MAPK/ERK kinase kinase kinase 4;
DE Short=MEK kinase kinase 4;
DE Short=MEKKK 4;
DE AltName: Full=Nck-interacting kinase;
GN Name=MAP4K4; Synonyms=HGK, KIAA0687, NIK;
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 {ECO:0000312|EMBL:AAD16137.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5), FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Macrophage;
RX PubMed=9890973; DOI=10.1074/jbc.274.4.2118;
RA Yao Z., Zhou G., Wang X.S., Brown A., Diener K., Gan H., Tan T.-H.;
RT "A novel human STE20-related protein kinase, HGK, that specifically
RT activates the c-Jun N-terminal kinase signaling pathway.";
RL J. Biol. Chem. 274:2118-2125(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Glioblastoma;
RX PubMed=12612079; DOI=10.1128/mcb.23.6.2068-2082.2003;
RA Wright J.H., Wang X., Manning G., LaMere B.J., Le P., Zhu S., Khatry D.,
RA Flanagan P.M., Buckley S.D., Whyte D.B., Howlett A.R., Bischoff J.R.,
RA Lipson K.E., Jallal B.;
RT "The STE20 kinase HGK is broadly expressed in human tumor cells and can
RT modulate cellular transformation, invasion, and adhesion.";
RL Mol. Cell. Biol. 23:2068-2082(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
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 [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 38-1239 (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 262-1239 (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] OF 700-1239.
RC TISSUE=Brain;
RA Saito T., Seki N., Hori T.;
RT "Isolation, expression profile and chromosome assignment of a novel
RT serine/threonine kinase gene.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP INTERACTION WITH ATL1.
RX PubMed=12387898; DOI=10.1016/s0014-5793(02)03467-1;
RA Luan Z., Zhang Y., Liu A., Man Y., Cheng L., Hu G.;
RT "A novel GTP-binding protein hGBP3 interacts with NIK/HGK.";
RL FEBS Lett. 530:233-238(2002).
RN [9]
RP INTERACTION WITH RAP2A, AND SUBCELLULAR LOCATION.
RX PubMed=14966141; DOI=10.1074/jbc.c300542200;
RA Machida N., Umikawa M., Takei K., Sakima N., Myagmar B.E., Taira K.,
RA Uezato H., Ogawa Y., Kariya K.;
RT "Mitogen-activated protein kinase kinase kinase kinase 4 as a putative
RT effector of Rap2 to activate the c-Jun N-terminal kinase.";
RL J. Biol. Chem. 279:15711-15714(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639; SER-644; SER-712 AND
RP SER-805, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-608 (ISOFORMS 2 AND
RP 6), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-716 (ISOFORM 3), AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629; SER-631; SER-639 AND
RP SER-805, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-608 AND SER-625
RP (ISOFORMS 2 AND 6), PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-716 AND
RP SER-733 (ISOFORM 3), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP 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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-5; SER-639; SER-644; SER-805 AND SER-900, CLEAVAGE OF
RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
RP 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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-800 AND SER-805, 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 [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-805, 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 [16]
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 [17]
RP FUNCTION.
RX PubMed=21690388; DOI=10.1073/pnas.1104128108;
RA Kaneko S., Chen X., Lu P., Yao X., Wright T.G., Rajurkar M., Kariya K.,
RA Mao J., Ip Y.T., Xu L.;
RT "Smad inhibition by the Ste20 kinase Misshapen.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:11127-11132(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629; SER-631 AND SER-639, 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 [19]
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=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629; SER-631; SER-639;
RP SER-700; SER-715; SER-800; SER-801; SER-805; SER-823; THR-828; SER-852;
RP SER-855 AND SER-913, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-639 AND SER-791, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] THR-712, AND VARIANT [LARGE SCALE ANALYSIS]
RP VAL-682 (ISOFORM 3).
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine kinase that may play a role in the response
CC to environmental stress and cytokines such as TNF-alpha. Appears to act
CC upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-
CC 322. {ECO:0000269|PubMed:21690388, ECO:0000269|PubMed:9890973}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:9890973};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:9890973};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:9890973};
CC -!- SUBUNIT: Interacts with the SH3 domain of the adapter proteins Nck (By
CC similarity). Interacts (via its CNH regulatory domain) with ATL1 (via
CC the N-terminal region). Interacts with RAP2A (GTP-bound form
CC preferentially). {ECO:0000250, ECO:0000269|PubMed:12387898,
CC ECO:0000269|PubMed:14966141}.
CC -!- INTERACTION:
CC O95819; Q9NRI5: DISC1; NbExp=2; IntAct=EBI-2511133, EBI-529989;
CC O95819; Q9H0R5: GBP3; NbExp=4; IntAct=EBI-2511133, EBI-2798916;
CC O95819; Q8N4C8: MINK1; NbExp=2; IntAct=EBI-2511133, EBI-2133481;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14966141}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1 {ECO:0000269|PubMed:9890973}; Synonyms=Tumor-associated;
CC IsoId=O95819-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:9890973};
CC IsoId=O95819-2; Sequence=VSP_007054, VSP_058855, VSP_007057;
CC Name=3 {ECO:0000269|PubMed:9890973};
CC IsoId=O95819-3; Sequence=VSP_007056, VSP_058855, VSP_007057;
CC Name=4 {ECO:0000269|PubMed:9890973}; Synonyms=HGK-S
CC {ECO:0000269|PubMed:9890973};
CC IsoId=O95819-4; Sequence=VSP_007054, VSP_007055, VSP_007057,
CC VSP_007058;
CC Name=5 {ECO:0000269|PubMed:9890973}; Synonyms=HGK-L
CC {ECO:0000269|PubMed:9890973};
CC IsoId=O95819-5; Sequence=VSP_007054, VSP_007055, VSP_007056,
CC VSP_007057, VSP_007058;
CC Name=6;
CC IsoId=O95819-6; Sequence=VSP_007054, VSP_058855, VSP_058856;
CC -!- TISSUE SPECIFICITY: Widely expressed. Isoform 5 is abundant in the
CC brain. Isoform 4 is predominant in the liver, skeletal muscle and
CC placenta. {ECO:0000269|PubMed:9890973}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
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DR EMBL; AF096300; AAD16137.1; -; mRNA.
DR EMBL; AY212247; AAO32626.1; -; mRNA.
DR EMBL; AC005035; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471127; EAX01810.1; -; Genomic_DNA.
DR EMBL; AC007005; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB014587; BAA31662.1; -; mRNA.
DR EMBL; AL137755; CAB70907.2; -; mRNA.
DR EMBL; AB013385; BAA33714.1; -; mRNA.
DR CCDS; CCDS56130.1; -. [O95819-1]
DR CCDS; CCDS74546.1; -. [O95819-6]
DR CCDS; CCDS82487.1; -. [O95819-4]
DR CCDS; CCDS92822.1; -. [O95819-2]
DR PIR; T46481; T46481.
DR RefSeq; NP_001229488.1; NM_001242559.1. [O95819-1]
DR RefSeq; NP_004825.3; NM_004834.4. [O95819-4]
DR RefSeq; NP_663719.2; NM_145686.3. [O95819-6]
DR RefSeq; NP_663720.1; NM_145687.3. [O95819-2]
DR PDB; 4OBO; X-ray; 2.10 A; A/B=2-328.
DR PDB; 4OBP; X-ray; 2.27 A; A/B=2-328.
DR PDB; 4OBQ; X-ray; 2.19 A; A/B=2-328.
DR PDB; 4RVT; X-ray; 2.40 A; A/B=1-325.
DR PDB; 4U3Y; X-ray; 1.45 A; A/B=2-328.
DR PDB; 4U3Z; X-ray; 2.09 A; A/B=2-328.
DR PDB; 4U40; X-ray; 2.30 A; A/B=2-328.
DR PDB; 4U41; X-ray; 2.20 A; A/B=2-328.
DR PDB; 4U42; X-ray; 2.50 A; A/B=2-328.
DR PDB; 4U43; X-ray; 2.18 A; A/B=2-328.
DR PDB; 4U44; X-ray; 2.43 A; A/B=2-328.
DR PDB; 4U45; X-ray; 2.58 A; A/B=2-328.
DR PDB; 4ZK5; X-ray; 2.89 A; A/B=2-328.
DR PDB; 4ZP5; X-ray; 2.29 A; A/B=1-309.
DR PDB; 5DI1; X-ray; 2.90 A; A/B=1-310.
DR PDB; 5J95; X-ray; 2.50 A; A/B=2-313.
DR PDB; 5W5Q; X-ray; 2.33 A; A/B=2-328.
DR PDBsum; 4OBO; -.
DR PDBsum; 4OBP; -.
DR PDBsum; 4OBQ; -.
DR PDBsum; 4RVT; -.
DR PDBsum; 4U3Y; -.
DR PDBsum; 4U3Z; -.
DR PDBsum; 4U40; -.
DR PDBsum; 4U41; -.
DR PDBsum; 4U42; -.
DR PDBsum; 4U43; -.
DR PDBsum; 4U44; -.
DR PDBsum; 4U45; -.
DR PDBsum; 4ZK5; -.
DR PDBsum; 4ZP5; -.
DR PDBsum; 5DI1; -.
DR PDBsum; 5J95; -.
DR PDBsum; 5W5Q; -.
DR AlphaFoldDB; O95819; -.
DR SMR; O95819; -.
DR BioGRID; 114838; 228.
DR IntAct; O95819; 69.
DR MINT; O95819; -.
DR STRING; 9606.ENSP00000343658; -.
DR BindingDB; O95819; -.
DR ChEMBL; CHEMBL6166; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; O95819; -.
DR GuidetoPHARMACOLOGY; 2088; -.
DR GlyCosmos; O95819; 1 site, 1 glycan.
DR GlyGen; O95819; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; O95819; -.
DR MetOSite; O95819; -.
DR PhosphoSitePlus; O95819; -.
DR SwissPalm; O95819; -.
DR BioMuta; MAP4K4; -.
DR CPTAC; CPTAC-1049; -.
DR CPTAC; CPTAC-866; -.
DR EPD; O95819; -.
DR jPOST; O95819; -.
DR MassIVE; O95819; -.
DR MaxQB; O95819; -.
DR PaxDb; 9606-ENSP00000343658; -.
DR PeptideAtlas; O95819; -.
DR ProteomicsDB; 18046; -.
DR ProteomicsDB; 51066; -. [O95819-1]
DR ProteomicsDB; 51067; -. [O95819-2]
DR ProteomicsDB; 51068; -. [O95819-3]
DR ProteomicsDB; 51069; -. [O95819-4]
DR ProteomicsDB; 51070; -. [O95819-5]
DR Pumba; O95819; -.
DR Antibodypedia; 2062; 780 antibodies from 38 providers.
DR DNASU; 9448; -.
DR Ensembl; ENST00000347699.8; ENSP00000314363.6; ENSG00000071054.17. [O95819-1]
DR Ensembl; ENST00000350878.9; ENSP00000343658.5; ENSG00000071054.17. [O95819-6]
DR Ensembl; ENST00000625522.3; ENSP00000486116.2; ENSG00000071054.17. [O95819-2]
DR Ensembl; ENST00000634702.1; ENSP00000489579.1; ENSG00000071054.17. [O95819-4]
DR GeneID; 9448; -.
DR KEGG; hsa:9448; -.
DR UCSC; uc002tbf.4; human.
DR UCSC; uc002tbg.4; human. [O95819-1]
DR AGR; HGNC:6866; -.
DR CTD; 9448; -.
DR DisGeNET; 9448; -.
DR GeneCards; MAP4K4; -.
DR HGNC; HGNC:6866; MAP4K4.
DR HPA; ENSG00000071054; Tissue enhanced (brain).
DR MIM; 604666; gene.
DR neXtProt; NX_O95819; -.
DR OpenTargets; ENSG00000071054; -.
DR PharmGKB; PA30612; -.
DR VEuPathDB; HostDB:ENSG00000071054; -.
DR eggNOG; KOG0587; Eukaryota.
DR GeneTree; ENSGT00940000155063; -.
DR InParanoid; O95819; -.
DR OMA; LEKRNGW; -.
DR OrthoDB; 2904475at2759; -.
DR PhylomeDB; O95819; -.
DR TreeFam; TF105138; -.
DR PathwayCommons; O95819; -.
DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR SignaLink; O95819; -.
DR SIGNOR; O95819; -.
DR BioGRID-ORCS; 9448; 27 hits in 1213 CRISPR screens.
DR ChiTaRS; MAP4K4; human.
DR GeneWiki; MAP4K4; -.
DR GenomeRNAi; 9448; -.
DR Pharos; O95819; Tchem.
DR PRO; PR:O95819; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; O95819; Protein.
DR Bgee; ENSG00000071054; Expressed in C1 segment of cervical spinal cord and 204 other cell types or tissues.
DR ExpressionAtlas; O95819; baseline and differential.
DR Genevisible; O95819; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; IDA:ARUK-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004111; F:creatine kinase activity; IDA:CACAO.
DR GO; GO:0008017; F:microtubule binding; IDA:ARUK-UCL.
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:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:CACAO.
DR GO; GO:0001953; P:negative regulation of cell-matrix adhesion; NAS:ARUK-UCL.
DR GO; GO:0048812; P:neuron projection morphogenesis; IBA:GO_Central.
DR GO; GO:0032014; P:positive regulation of ARF protein signal transduction; ISS:ARUK-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ARUK-UCL.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; ISS:ARUK-UCL.
DR GO; GO:0120183; P:positive regulation of focal adhesion disassembly; ISS:ARUK-UCL.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:ARUK-UCL.
DR GO; GO:0051549; P:positive regulation of keratinocyte migration; ISS:ARUK-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0046328; P:regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR001180; CNH_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR47096:SF1; CNH DOMAIN-CONTAINING PROTEIN; 1.
DR PANTHER; PTHR47096; MISSHAPEN LIKE KINASE 1; 1.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00036; CNH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR PROSITE; PS50219; CNH; 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; ATP-binding; Cytoplasm;
KW Kinase; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..1239
FT /note="Mitogen-activated protein kinase kinase kinase
FT kinase 4"
FT /id="PRO_0000086280"
FT DOMAIN 25..289
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 926..1213
FT /note="CNH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00795"
FT REGION 306..349
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 421..462
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 517..811
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 858..1212
FT /note="Mediates interaction with RAP2A"
FT /evidence="ECO:0000269|PubMed:14966141"
FT COMPBIAS 306..320
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 321..337
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 550..579
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 598..612
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 622..660
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 676..719
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 722..737
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 770..789
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 793..811
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 153
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 31..39
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 54
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 5
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 324
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97820"
FT MOD_RES 326
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97820"
FT MOD_RES 629
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 631
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 639
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18220336,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 644
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195"
FT MOD_RES 656
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97820"
FT MOD_RES 700
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 712
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 715
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 791
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 800
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 801
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 805
FT /note="Phosphoserine"
FT /evidence="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:23186163"
FT MOD_RES 823
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 828
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 852
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 855
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 900
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 913
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 495..525
FT /note="Missing (in isoform 2, isoform 4, isoform 5 and
FT isoform 6)"
FT /evidence="ECO:0000303|PubMed:9734811,
FT ECO:0000303|PubMed:9890973, ECO:0000305"
FT /id="VSP_007054"
FT VAR_SEQ 569..622
FT /note="Missing (in isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:9890973"
FT /id="VSP_007055"
FT VAR_SEQ 623
FT /note="V -> VQWSHLASLKNNVSPVSRSHSFSDPSPKFAHHHLRSQDPCPPSRSEV
FT LSQSSDSKSEAPDPTQKAWSRSDSDEVPPRV (in isoform 3 and isoform
FT 5)"
FT /evidence="ECO:0000303|PubMed:17974005,
FT ECO:0000303|PubMed:9890973"
FT /id="VSP_007056"
FT VAR_SEQ 659
FT /note="I -> SI (in isoform 2, isoform 3 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:17974005,
FT ECO:0000303|PubMed:9734811, ECO:0000305"
FT /id="VSP_058855"
FT VAR_SEQ 740
FT /note="A -> AGEV (in isoform 2, isoform 3, isoform 4 and
FT isoform 5)"
FT /evidence="ECO:0000303|PubMed:17974005,
FT ECO:0000303|PubMed:9734811, ECO:0000303|PubMed:9890973"
FT /id="VSP_007057"
FT VAR_SEQ 839
FT /note="Q -> QSTVDQKRASHHESNGFAGRIHLLPDLLQQSHSSSTSSTSSSPSSSQ
FT PTPTMSPQTPQDKLTANE (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_058856"
FT VAR_SEQ 1112
FT /note="H -> HVRKNPHSM (in isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:9890973"
FT /id="VSP_007058"
FT VARIANT 712
FT /note="S -> T"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040746"
FT CONFLICT 839
FT /note="Q -> R (in Ref. 2; AAO32626)"
FT /evidence="ECO:0000305"
FT HELIX 15..17
FT /evidence="ECO:0007829|PDB:4U43"
FT TURN 22..24
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 25..33
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 35..44
FT /evidence="ECO:0007829|PDB:4U3Y"
FT TURN 45..47
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 50..58
FT /evidence="ECO:0007829|PDB:4U3Y"
FT TURN 60..62
FT /evidence="ECO:0007829|PDB:4ZP5"
FT HELIX 63..73
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 74..77
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 79..82
FT /evidence="ECO:0007829|PDB:4U42"
FT STRAND 85..91
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 99..105
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 113..118
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 127..146
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 156..158
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 167..170
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 174..180
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:4U3Z"
FT HELIX 197..199
FT /evidence="ECO:0007829|PDB:4U3Y"
FT STRAND 205..207
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 214..228
FT /evidence="ECO:0007829|PDB:4U3Y"
FT TURN 232..235
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 238..244
FT /evidence="ECO:0007829|PDB:4U3Y"
FT TURN 245..247
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 260..269
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 274..276
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 280..284
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 287..290
FT /evidence="ECO:0007829|PDB:4U3Y"
FT HELIX 295..310
FT /evidence="ECO:0007829|PDB:4U3Y"
FT MOD_RES O95819-2:608
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES O95819-2:625
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES O95819-3:716
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES O95819-3:733
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT VARIANT O95819-3:682
FT /note="D -> V"
FT /evidence="ECO:0007744|PubMed:17344846"
FT /id="VAR_082893"
FT MOD_RES O95819-6:608
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES O95819-6:625
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
SQ SEQUENCE 1239 AA; 142101 MW; 8FBBE2F9ABEEC757 CRC64;
MANDSPAKSL VDIDLSSLRD PAGIFELVEV VGNGTYGQVY KGRHVKTGQL AAIKVMDVTE
DEEEEIKLEI NMLKKYSHHR NIATYYGAFI KKSPPGHDDQ LWLVMEFCGA GSITDLVKNT
KGNTLKEDWI AYISREILRG LAHLHIHHVI HRDIKGQNVL LTENAEVKLV DFGVSAQLDR
TVGRRNTFIG TPYWMAPEVI ACDENPDATY DYRSDLWSCG ITAIEMAEGA PPLCDMHPMR
ALFLIPRNPP PRLKSKKWSK KFFSFIEGCL VKNYMQRPST EQLLKHPFIR DQPNERQVRI
QLKDHIDRTR KKRGEKDETE YEYSGSEEEE EEVPEQEGEP SSIVNVPGES TLRRDFLRLQ
QENKERSEAL RRQQLLQEQQ LREQEEYKRQ LLAERQKRIE QQKEQRRRLE EQQRREREAR
RQQEREQRRR EQEEKRRLEE LERRRKEEEE RRRAEEEKRR VEREQEYIRR QLEEEQRHLE
VLQQQLLQEQ AMLLECRWRE MEEHRQAERL QRQLQQEQAY LLSLQHDHRR PHPQHSQQPP
PPQQERSKPS FHAPEPKAHY EPADRAREVE DRFRKTNHSS PEAQSKQTGR VLEPPVPSRS
ESFSNGNSES VHPALQRPAE PQVPVRTTSR SPVLSRRDSP LQGSGQQNSQ AGQRNSTSIE
PRLLWERVEK LVPRPGSGSS SGSSNSGSQP GSHPGSQSGS GERFRVRSSS KSEGSPSQRL
ENAVKKPEDK KEVFRPLKPA DLTALAKELR AVEDVRPPHK VTDYSSSSEE SGTTDEEDDD
VEQEGADEST SGPEDTRAAS SLNLSNGETE SVKTMIVHDD VESEPAMTPS KEGTLIVRQT
QSASSTLQKH KSSSSFTPFI DPRLLQISPS SGTTVTSVVG FSCDGMRPEA IRQDPTRKGS
VVNVNPTNTR PQSDTPEIRK YKKRFNSEIL CAALWGVNLL VGTESGLMLL DRSGQGKVYP
LINRRRFQQM DVLEGLNVLV TISGKKDKLR VYYLSWLRNK ILHNDPEVEK KQGWTTVGDL
EGCVHYKVVK YERIKFLVIA LKSSVEVYAW APKPYHKFMA FKSFGELVHK PLLVDLTVEE
GQRLKVIYGS CAGFHAVDVD SGSVYDIYLP THIQCSIKPH AIIILPNTDG MELLVCYEDE
GVYVNTYGRI TKDVVLQWGE MPTSVAYIRS NQTMGWGEKA IEIRSVETGH LDGVFMHKRA
QRLKFLCERN DKVFFASVRS GGSSQVYFMT LGRTSLLSW
//
