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   27-MAR-2024, entry version 194.
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=5; 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}.
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DR   EMBL; U77129; AAB48435.1; -; mRNA.
DR   EMBL; BC036013; AAH36013.1; -; mRNA.
DR   EMBL; AL118556; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS91875.1; -.
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; 94.
DR   IntAct; Q9Y4K4; 26.
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; 9606-ENSP00000013125; -.
DR   PeptideAtlas; Q9Y4K4; -.
DR   ProteomicsDB; 86226; -.
DR   Pumba; Q9Y4K4; -.
DR   Antibodypedia; 23648; 217 antibodies from 26 providers.
DR   DNASU; 11183; -.
DR   Ensembl; ENST00000013125.9; ENSP00000013125.5; ENSG00000012983.12.
DR   GeneID; 11183; -.
DR   KEGG; hsa:11183; -.
DR   AGR; HGNC:6867; -.
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; XQYIIFG; -.
DR   OrthoDB; 152877at2759; -.
DR   PhylomeDB; Q9Y4K4; -.
DR   TreeFam; TF105121; -.
DR   PathwayCommons; Q9Y4K4; -.
DR   SignaLink; Q9Y4K4; -.
DR   SIGNOR; Q9Y4K4; -.
DR   BioGRID-ORCS; 11183; 21 hits in 423 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 200 other cell types or tissues.
DR   ExpressionAtlas; Q9Y4K4; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
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:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   CDD; cd06646; STKc_MAP4K5; 1.
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; IPR021160; MAPKKKK.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   PANTHER; PTHR48012:SF19; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 5; 1.
DR   PANTHER; PTHR48012; STERILE20-LIKE KINASE, ISOFORM B-RELATED; 1.
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; 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.
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
//