M4K5_HUMAN
ID M4K5_HUMAN Reviewed; 846 AA.
AC Q9Y4K4; A0A0A0MQR1; Q8IYF6;
DT 30-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 31-JAN-2018, sequence version 2.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 5;
DE EC=2.7.11.1;
DE AltName: Full=Kinase homologous to SPS1/STE20;
DE Short=KHS;
DE AltName: Full=MAPK/ERK kinase kinase kinase 5;
DE Short=MEK kinase kinase 5;
DE Short=MEKKK 5;
GN Name=MAP4K5;
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:AAB48435.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, MUTAGENESIS OF LYS-49, AND VARIANT ASN-473.
RC TISSUE=T-cell;
RX PubMed=9038372; DOI=10.1038/sj.onc.1200877;
RA Tung R.M., Blenis J.;
RT "A novel human SPS1/STE20 homologue, KHS, activates jun N-terminal
RT kinase.";
RL Oncogene 14:653-659(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [4]
RP INTERACTION WITH CRK AND CRKL.
RX PubMed=9788432; DOI=10.1038/sj.onc.1202108;
RA Oehrl W., Kardinal C., Ruf S., Adermann K., Groffen J., Feng G.-S.,
RA Blenis J., Tan T.-H., Feller S.M.;
RT "The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are
RT candidates for highly selective signal transducers of Crk family adapter
RT proteins.";
RL Oncogene 17:1893-1901(1998).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-335, 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 [7]
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 [8]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-334; LEU-407; VAL-446; GLN-552 AND
RP MET-633.
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: May play a role in the response to environmental stress.
CC Appears to act upstream of the JUN N-terminal pathway.
CC {ECO:0000269|PubMed:9038372}.
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:9038372};
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:9038372};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:9038372};
CC -!- SUBUNIT: Interacts with both SH3 domains of the adapter proteins CRK
CC and CRKL. {ECO:0000269|PubMed:9788432}.
CC -!- INTERACTION:
CC Q9Y4K4; P46108: CRK; NbExp=6; IntAct=EBI-1279, EBI-886;
CC Q9Y4K4; P62993: GRB2; NbExp=6; IntAct=EBI-1279, EBI-401755;
CC Q9Y4K4; P16333: NCK1; NbExp=2; IntAct=EBI-1279, EBI-389883;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9038372}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in all tissues examined,
CC with high levels in the ovary, testis and prostate.
CC {ECO:0000269|PubMed:9038372}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U77129; AAB48435.1; -; mRNA.
DR EMBL; BC036013; AAH36013.1; -; mRNA.
DR EMBL; AL118556; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_006566.2; NM_006575.4.
DR RefSeq; NP_942089.1; NM_198794.2.
DR RefSeq; XP_006720076.1; XM_006720013.3.
DR AlphaFoldDB; Q9Y4K4; -.
DR SMR; Q9Y4K4; -.
DR BioGRID; 116353; 67.
DR IntAct; Q9Y4K4; 17.
DR MINT; Q9Y4K4; -.
DR STRING; 9606.ENSP00000013125; -.
DR BindingDB; Q9Y4K4; -.
DR ChEMBL; CHEMBL4852; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9Y4K4; -.
DR GuidetoPHARMACOLOGY; 2089; -.
DR iPTMnet; Q9Y4K4; -.
DR MetOSite; Q9Y4K4; -.
DR PhosphoSitePlus; Q9Y4K4; -.
DR BioMuta; MAP4K5; -.
DR DMDM; 30316147; -.
DR CPTAC; CPTAC-868; -.
DR CPTAC; CPTAC-869; -.
DR EPD; Q9Y4K4; -.
DR jPOST; Q9Y4K4; -.
DR MassIVE; Q9Y4K4; -.
DR PaxDb; Q9Y4K4; -.
DR PeptideAtlas; Q9Y4K4; -.
DR PRIDE; Q9Y4K4; -.
DR ProteomicsDB; 86226; -.
DR Antibodypedia; 23648; 181 antibodies from 25 providers.
DR DNASU; 11183; -.
DR Ensembl; ENST00000013125.9; ENSP00000013125.5; ENSG00000012983.12.
DR GeneID; 11183; -.
DR KEGG; hsa:11183; -.
DR CTD; 11183; -.
DR DisGeNET; 11183; -.
DR GeneCards; MAP4K5; -.
DR HGNC; HGNC:6867; MAP4K5.
DR HPA; ENSG00000012983; Low tissue specificity.
DR MIM; 604923; gene.
DR neXtProt; NX_Q9Y4K4; -.
DR PharmGKB; PA30613; -.
DR VEuPathDB; HostDB:ENSG00000012983; -.
DR eggNOG; KOG0576; Eukaryota.
DR InParanoid; Q9Y4K4; -.
DR OMA; NPSHMFT; -.
DR OrthoDB; 996262at2759; -.
DR PhylomeDB; Q9Y4K4; -.
DR TreeFam; TF105121; -.
DR PathwayCommons; Q9Y4K4; -.
DR SignaLink; Q9Y4K4; -.
DR SIGNOR; Q9Y4K4; -.
DR BioGRID-ORCS; 11183; 14 hits in 351 CRISPR screens.
DR ChiTaRS; MAP4K5; human.
DR GeneWiki; MAP4K5; -.
DR GenomeRNAi; 11183; -.
DR Pharos; Q9Y4K4; Tchem.
DR PRO; PR:Q9Y4K4; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9Y4K4; protein.
DR Bgee; ENSG00000012983; Expressed in corpus callosum and 198 other tissues.
DR ExpressionAtlas; Q9Y4K4; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0008349; F:MAP kinase kinase 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; IDA:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR InterPro; IPR001180; CNH_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR021160; MAPKKKK.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038172; MAPKKKK; 1.
DR SMART; SM00036; CNH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50219; CNH; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..846
FT /note="Mitogen-activated protein kinase kinase kinase
FT kinase 5"
FT /id="PRO_0000086282"
FT DOMAIN 20..277
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 506..819
FT /note="CNH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00795"
FT REGION 323..485
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 333..358
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 402..418
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 426..466
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 140
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 26..34
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 49
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:9038372"
FT MOD_RES 335
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 433
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BPM2"
FT VARIANT 41
FT /note="H -> Y (in dbSNP:rs34726242)"
FT /id="VAR_057102"
FT VARIANT 334
FT /note="A -> T (in dbSNP:rs12881869)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040747"
FT VARIANT 407
FT /note="P -> L (in dbSNP:rs34818002)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040748"
FT VARIANT 446
FT /note="I -> V (in dbSNP:rs55815015)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040749"
FT VARIANT 473
FT /note="K -> N (in dbSNP:rs35768475)"
FT /evidence="ECO:0000269|PubMed:9038372"
FT /id="VAR_040750"
FT VARIANT 552
FT /note="R -> Q (in dbSNP:rs55997280)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040751"
FT VARIANT 633
FT /note="T -> M (in dbSNP:rs17780143)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040752"
FT MUTAGEN 49
FT /note="K->R: Loss of kinase activity and ability to
FT activate JNK family."
FT /evidence="ECO:0000269|PubMed:9038372"
FT CONFLICT 569
FT /note="V -> E (in Ref. 1; AAB48435 and 3; AAH36013)"
SQ SEQUENCE 846 AA; 95024 MW; 4E74B9BD9BA62272 CRC64;
MEAPLRPAAD ILRRNPQQDY ELVQRVGSGT YGDVYKARNV HTGELAAVKI IKLEPGDDFS
LIQQEIFMVK ECKHCNIVAY FGSYLSREKL WICMEYCGGG SLQDIYHVTG PLSELQIAYV
CRETLQGLAY LHTKGKMHRD IKGANILLTD HGDVKLADFG VAAKITATIA KRKSFIGTPY
WMAPEVAAVE KNGGYNQLCD IWAVGITAIE LGELQPPMFD LHPMRALFLM SKSNFQPPKL
KDKTKWSSTF HNFVKIALTK NPKKRPTAER LLTHTFVAQP GLSRALAVEL LDKVNNPDNH
AHYTEADDDD FEPHAIIRHT IRSTNRNARA ERTASEINFD KLQFEPPLRK ETEARDEMGL
SSDPNFMLQW NPFVDGANTG KSTSKRAIPP PLPPKPRISS YPEDNFPDEE KASTIKHCPD
SESRAPQILR RQSSPSCGPV AETSSIGNGD GISKLMSENT EGSAQAPQLP RKKDKRDFPK
PAINGLPPTP KVLMGACFSK VFDGCPLKIN CATSWIHPDT KDQYIIFGTE DGIYTLNLNE
LHEATMEQLF PRKCTWLYVI NNTLMSLSVG KTFQLYSHNL IALFEHAKKP GLAAHIQTHR
FPDRILPRKF ALTTKIPDTK GCHKCCIVRN PYTGHKYLCG ALQSGIVLLQ WYEPMQKFML
IKHFDFPLPS PLNVFEMLVI PEQEYPMVCV AISKGTESNQ VVQFETINLN SASSWFTEIG
AGSQQLDSIH VTQLERDTVL VCLDKFVKIV NLQGKLKSSK KLASELSFDF RIESVVCLQD
SVLAFWKHGM QGKSFKSDEV TQEISDETRV FRLLGSDRVV VLESRPTENP TAHSNLYILA
GHENSY
