M3K10_HUMAN
ID M3K10_HUMAN Reviewed; 954 AA.
AC Q02779; Q12761; Q14871;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 3.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 10;
DE EC=2.7.11.25;
DE AltName: Full=Mixed lineage kinase 2;
DE AltName: Full=Protein kinase MST;
GN Name=MAP3K10; Synonyms=MLK2, MST;
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].
RC TISSUE=Brain;
RX PubMed=8536694; DOI=10.1111/j.1432-1033.1995.492_b.x;
RA Dorow D.S., Devereux L., Tu G.F., Price G., Nicholl J.K., Sutherland G.R.,
RA Simpson R.J.;
RT "Complete nucleotide sequence, expression, and chromosomal localisation of
RT human mixed-lineage kinase 2.";
RL Eur. J. Biochem. 234:492-500(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=7731697;
RA Katoh M., Hirai M., Sugimura T., Terada M.;
RT "Cloning and characterization of MST, a novel (putative) serine/threonine
RT kinase with SH3 domain.";
RL Oncogene 10:1447-1451(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-480.
RC TISSUE=Colon epithelium;
RX PubMed=8477742; DOI=10.1111/j.1432-1033.1993.tb17810.x;
RA Dorow D.S., Devereux L., Dietzsch E., de Kretser T.;
RT "Identification of a new family of human epithelial protein kinases
RT containing two leucine/isoleucine-zipper domains.";
RL Eur. J. Biochem. 213:701-710(1993).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-498; SER-502 AND THR-558, AND
RP IDENTIFICATION BY 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 [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-506, AND IDENTIFICATION BY
RP 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 [6]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-107.
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: Activates the JUN N-terminal pathway. {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Homodimerization via the leucine zipper domains is
CC required for autophosphorylation and subsequent activation.
CC {ECO:0000250}.
CC -!- SUBUNIT: Homodimer. Interacts with SH3RF2. {ECO:0000250,
CC ECO:0000250|UniProtKB:D3ZG83}.
CC -!- INTERACTION:
CC Q02779; Q5TCX8: MAP3K21; NbExp=3; IntAct=EBI-3392815, EBI-1057380;
CC -!- TISSUE SPECIFICITY: Expressed in brain and skeletal muscle.
CC -!- PTM: Autophosphorylation on serine and threonine residues within the
CC activation loop plays a role in enzyme activation. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {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; X90846; CAA62351.1; -; mRNA.
DR EMBL; Z48615; CAA88531.1; -; mRNA.
DR CCDS; CCDS12549.1; -.
DR PIR; S68178; S68178.
DR RefSeq; NP_002437.2; NM_002446.3.
DR PDB; 2RF0; X-ray; 2.00 A; A/B/C/D=13-78.
DR PDBsum; 2RF0; -.
DR AlphaFoldDB; Q02779; -.
DR SMR; Q02779; -.
DR BioGRID; 110440; 40.
DR ELM; Q02779; -.
DR IntAct; Q02779; 15.
DR STRING; 9606.ENSP00000253055; -.
DR BindingDB; Q02779; -.
DR ChEMBL; CHEMBL2873; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q02779; -.
DR GuidetoPHARMACOLOGY; 2070; -.
DR iPTMnet; Q02779; -.
DR PhosphoSitePlus; Q02779; -.
DR BioMuta; MAP3K10; -.
DR DMDM; 145559494; -.
DR jPOST; Q02779; -.
DR MassIVE; Q02779; -.
DR MaxQB; Q02779; -.
DR PaxDb; Q02779; -.
DR PeptideAtlas; Q02779; -.
DR PRIDE; Q02779; -.
DR ProteomicsDB; 58124; -.
DR TopDownProteomics; Q02779; -.
DR Antibodypedia; 2053; 266 antibodies from 33 providers.
DR DNASU; 4294; -.
DR Ensembl; ENST00000253055.8; ENSP00000253055.2; ENSG00000130758.8.
DR GeneID; 4294; -.
DR KEGG; hsa:4294; -.
DR MANE-Select; ENST00000253055.8; ENSP00000253055.2; NM_002446.4; NP_002437.2.
DR UCSC; uc002ona.3; human.
DR CTD; 4294; -.
DR DisGeNET; 4294; -.
DR GeneCards; MAP3K10; -.
DR HGNC; HGNC:6849; MAP3K10.
DR HPA; ENSG00000130758; Tissue enhanced (brain).
DR MIM; 600137; gene.
DR neXtProt; NX_Q02779; -.
DR OpenTargets; ENSG00000130758; -.
DR PharmGKB; PA30593; -.
DR VEuPathDB; HostDB:ENSG00000130758; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000160518; -.
DR HOGENOM; CLU_000288_7_14_1; -.
DR InParanoid; Q02779; -.
DR OMA; CNQRKKS; -.
DR OrthoDB; 115270at2759; -.
DR PhylomeDB; Q02779; -.
DR TreeFam; TF105118; -.
DR PathwayCommons; Q02779; -.
DR SABIO-RK; Q02779; -.
DR SignaLink; Q02779; -.
DR SIGNOR; Q02779; -.
DR BioGRID-ORCS; 4294; 10 hits in 1114 CRISPR screens.
DR ChiTaRS; MAP3K10; human.
DR EvolutionaryTrace; Q02779; -.
DR GeneWiki; MAP3K10; -.
DR GenomeRNAi; 4294; -.
DR Pharos; Q02779; Tchem.
DR PRO; PR:Q02779; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q02779; protein.
DR Bgee; ENSG00000130758; Expressed in right frontal lobe and 125 other tissues.
DR ExpressionAtlas; Q02779; baseline and differential.
DR Genevisible; Q02779; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043425; F:bHLH transcription factor binding; IPI:UniProtKB.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
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:0003714; F:transcription corepressor activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0007254; P:JNK cascade; TAS:ProtInc.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IMP:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0007224; P:smoothened signaling pathway; IMP:UniProtKB.
DR CDD; cd12059; SH3_MLK1-3; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR015785; MAP3K10.
DR InterPro; IPR035779; MLK1-3_SH3.
DR InterPro; IPR016231; MLK1-4.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR PANTHER; PTHR44329:SF39; PTHR44329:SF39; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR PIRSF; PIRSF000556; MAPKKK9_11; 1.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF50044; SSF50044; 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.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Kinase; Methylation; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; SH3 domain; Transferase.
FT CHAIN 1..954
FT /note="Mitogen-activated protein kinase kinase kinase 10"
FT /id="PRO_0000086259"
FT DOMAIN 16..81
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 98..360
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 384..405
FT /note="Leucine-zipper 1"
FT REGION 419..440
FT /note="Leucine-zipper 2"
FT REGION 490..665
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 716..739
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 757..954
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 523..538
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 644..658
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 771..790
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 933..948
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 222
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 104..112
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 125
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 258
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 262
FT /note="Phosphoserine; by autocatalysis and MAP4K1"
FT /evidence="ECO:0000250"
FT MOD_RES 498
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 502
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 506
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 558
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 857
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q66L42"
FT VARIANT 107
FT /note="G -> E (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040702"
FT VARIANT 168
FT /note="P -> Q (in dbSNP:rs36102209)"
FT /id="VAR_051639"
FT CONFLICT 462..464
FT /note="SRL -> AV (in Ref. 2; CAA88531)"
FT /evidence="ECO:0000305"
FT CONFLICT 465..480
FT /note="LKLREGGSHISLPSGF -> AQAAGRRQPHQPALWL (in Ref. 3)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="G -> S (in Ref. 2; CAA88531)"
FT /evidence="ECO:0000305"
FT CONFLICT 807
FT /note="R -> G (in Ref. 1; CAA62351)"
FT /evidence="ECO:0000305"
FT CONFLICT 818
FT /note="A -> V (in Ref. 1; CAA62351)"
FT /evidence="ECO:0000305"
FT STRAND 20..23
FT /evidence="ECO:0007829|PDB:2RF0"
FT STRAND 42..47
FT /evidence="ECO:0007829|PDB:2RF0"
FT HELIX 50..53
FT /evidence="ECO:0007829|PDB:2RF0"
FT STRAND 58..62
FT /evidence="ECO:0007829|PDB:2RF0"
FT STRAND 68..72
FT /evidence="ECO:0007829|PDB:2RF0"
FT HELIX 73..75
FT /evidence="ECO:0007829|PDB:2RF0"
SQ SEQUENCE 954 AA; 103694 MW; 59A7596B05751981 CRC64;
MEEEEGAVAK EWGTTPAGPV WTAVFDYEAA GDEELTLRRG DRVQVLSQDC AVSGDEGWWT
GQLPSGRVGV FPSNYVAPGA PAAPAGLQLP QEIPFHELQL EEIIGVGGFG KVYRALWRGE
EVAVKAARLD PEKDPAVTAE QVCQEARLFG ALQHPNIIAL RGACLNPPHL CLVMEYARGG
ALSRVLAGRR VPPHVLVNWA VQVARGMNYL HNDAPVPIIH RDLKSINILI LEAIENHNLA
DTVLKITDFG LAREWHKTTK MSAAGTYAWM APEVIRLSLF SKSSDVWSFG VLLWELLTGE
VPYREIDALA VAYGVAMNKL TLPIPSTCPE PFARLLEECW DPDPHGRPDF GSILKRLEVI
EQSALFQMPL ESFHSLQEDW KLEIQHMFDD LRTKEKELRS REEELLRAAQ EQRFQEEQLR
RREQELAERE MDIVERELHL LMCQLSQEKP RVRKRKGNFK RSRLLKLREG GSHISLPSGF
EHKITVQASP TLDKRKGSDG ASPPASPSII PRLRAIRLTP VDCGGSSSGS SSGGSGTWSR
GGPPKKEELV GGKKKGRTWG PSSTLQKERV GGEERLKGLG EGSKQWSSSA PNLGKSPKHT
PIAPGFASLN EMEEFAEAED GGSSVPPSPY STPSYLSVPL PAEPSPGARA PWEPTPSAPP
ARWGHGARRR CDLALLGCAT LLGAVGLGAD VAEARAADGE EQRRWLDGLF FPRAGRFPRG
LSPPARPHGR REDVGPGLGL APSATLVSLS SVSDCNSTRS LLRSDSDEAA PAAPSPPPSP
PAPTPTPSPS TNPLVDLELE SFKKDPRQSL TPTHVTAACA VSRGHRRTPS DGALGQRGPP
EPAGHGPGPR DLLDFPRLPD PQALFPARRR PPEFPGRPTT LTFAPRPRPA ASRPRLDPWK
LVSFGRTLTI SPPSRPDTPE SPGPPSVQPT LLDMDMEGQN QDSTVPLCGA HGSH
