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P80192 (M3K9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 9

EC=2.7.11.25
Alternative name(s):
Mixed lineage kinase 1
Gene names
Name:MAP3K9
Synonyms:MLK1, PRKE1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1104 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Ref.1 Ref.6 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Enzyme regulation

Homodimerization via the leucine zipper domains is required for autophosphorylation of multiple sites in the activation loop and subsequent activation. Autophosphorylation at Thr-312 is the key step in activation of MAP3K9/MLK1 and is required for full phosphorylation. Autophosphorylation at Thr-304 and Ser-308 have been shown to be of secondary importance in the activation of MAP3K9/MLK1. CEP-1347 and many indolocarbazole analogs have been shown to act as inhibitors of MAP3K9/MLK1 activity. Ref.1 Ref.5 Ref.7

Subunit structure

Homodimer By similarity.

Tissue specificity

Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. Ref.4

Post-translational modification

Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-312 is likely to be the main autophosphorylation site. Autophosphorylation also occurs on Thr-304 and Ser-308.

Involvement in disease

May play a role in esophageal cancer susceptibility and/or development.

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Contains 1 SH3 domain.

Biophysicochemical properties

Kinetic parameters:

KM=62 µM for ATP Ref.5

KM=7 µM for myelin basic protein (MBP) as substrate

Sequence caution

The sequence AAI11408.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
   Biological processApoptosis
Stress response
Transcription
Transcription regulation
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainRepeat
SH3 domain
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of JNKK activity

Inferred from sequence or structural similarity. Source: GOC

activation of JUN kinase activity

Inferred from sequence or structural similarity PubMed 8195146. Source: UniProtKB

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from direct assay Ref.1. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.1. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

JUN kinase kinase kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

MAP kinase kinase activity

Non-traceable author statement Ref.4. Source: UniProtKB

protein homodimerization activity

Inferred from sequence or structural similarity PubMed 8195146. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.1. Source: UniProtKB

protein tyrosine kinase activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

HSP90AB1P082382EBI-3951604,EBI-352572

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P80192-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P80192-4)

The sequence of this isoform differs from the canonical sequence as follows:
     675-675: M → MALLAASWVVPIDIE

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 11041104Mitogen-activated protein kinase kinase kinase 9
PRO_0000086258

Regions

Domain52 – 11665SH3
Domain144 – 412269Protein kinase
Nucleotide binding150 – 1589ATP By similarity
Region430 – 45122Leucine-zipper 1
Region465 – 48622Leucine-zipper 2
Compositional bias12 – 4231Ala-rich
Compositional bias30 – 389Poly-Glu
Compositional bias495 – 50915Arg/Lys-rich (basic)
Compositional bias863 – 972110Pro-rich
Compositional bias1011 – 104131Ser-rich

Sites

Active site2681Proton acceptor By similarity
Binding site1711ATP

Amino acid modifications

Modified residue3041Phosphothreonine; by autocatalysis Ref.1
Modified residue3051Phosphothreonine; by autocatalysis Ref.1
Modified residue3081Phosphoserine; by autocatalysis Ref.1
Modified residue3121Phosphothreonine; by autocatalysis Ref.1

Natural variations

Alternative sequence6751M → MALLAASWVVPIDIE in isoform 2.
VSP_013765
Natural variant2461A → V in a metastatic melanoma sample; somatic mutation. Ref.11
VAR_040698
Natural variant4671R → C in a gastric adenocarcinoma sample; somatic mutation. Ref.11
VAR_040699
Natural variant4971R → Q. Ref.11
Corresponds to variant rs56196343 [ dbSNP | Ensembl ].
VAR_040700
Natural variant6461Y → C. Ref.11
Corresponds to variant rs34322726 [ dbSNP | Ensembl ].
VAR_040701

Experimental info

Mutagenesis1711K → A: Loss of kinase activity and threonine phosphorylation. Ref.1
Mutagenesis3041T → A: Reduces threonine phosphorylation. Impairs JNK activation. Ref.1
Mutagenesis3051T → A: Little effect on threonine phosphorylation. Mildly impairs JNK activation. Ref.1
Mutagenesis3081S → A: Impairs JNK activation. Ref.1
Mutagenesis3121T → A: Loss of threonine phosphorylation. Strongly impairs JNK activation. Ref.1
Sequence conflict3561A → R Ref.4
Sequence conflict4331M → T in AAQ23054. Ref.1
Sequence conflict511 – 53525KLKDG…QASPT → AQPVLPFPHGHSRCPGGTGS SWGGQ Ref.4

Secondary structure

......................................... 1104
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 17, 2006. Version 3.
Checksum: 0F059C867FCE7276

FASTA1,104121,895
        10         20         30         40         50         60 
MEPSRALLGC LASAAAAAPP GEDGAGAGAE EEEEEEEEAA AAVGPGELGC DAPLPYWTAV 

        70         80         90        100        110        120 
FEYEAAGEDE LTLRLGDVVE VLSKDSQVSG DEGWWTGQLN QRVGIFPSNY VTPRSAFSSR 

       130        140        150        160        170        180 
CQPGGEDPSC YPPIQLLEID FAELTLEEII GIGGFGKVYR AFWIGDEVAV KAARHDPDED 

       190        200        210        220        230        240 
ISQTIENVRQ EAKLFAMLKH PNIIALRGVC LKEPNLCLVM EFARGGPLNR VLSGKRIPPD 

       250        260        270        280        290        300 
ILVNWAVQIA RGMNYLHDEA IVPIIHRDLK SSNILILQKV ENGDLSNKIL KITDFGLARE 

       310        320        330        340        350        360 
WHRTTKMSAA GTYAWMAPEV IRASMFSKGS DVWSYGVLLW ELLTGEVPFR GIDGLAVAYG 

       370        380        390        400        410        420 
VAMNKLALPI PSTCPEPFAK LMEDCWNPDP HSRPSFTNIL DQLTTIEESG FFEMPKDSFH 

       430        440        450        460        470        480 
CLQDNWKHEI QEMFDQLRAK EKELRTWEEE LTRAALQQKN QEELLRRREQ ELAEREIDIL 

       490        500        510        520        530        540 
ERELNIIIHQ LCQEKPRVKK RKGKFRKSRL KLKDGNRISL PSDFQHKFTV QASPTMDKRK 

       550        560        570        580        590        600 
SLINSRSSPP ASPTIIPRLR AIQLTPGESS KTWGRSSVVP KEEGEEEEKR APKKKGRTWG 

       610        620        630        640        650        660 
PGTLGQKELA SGDEGSPQRR EKANGLSTPS ESPHFHLGLK SLVDGYKQWS SSAPNLVKGP 

       670        680        690        700        710        720 
RSSPALPGFT SLMEMEDEDS EGPGSGESRL QHSPSQSYLC IPFPRGEDGD GPSSDGIHEE 

       730        740        750        760        770        780 
PTPVNSATST PQLTPTNSLK RGGAHHRRCE VALLGCGAVL AATGLGFDLL EAGKCQLLPL 

       790        800        810        820        830        840 
EEPEPPAREE KKRREGLFQR SSRPRRSTSP PSRKLFKKEE PMLLLGDPSA SLTLLSLSSI 

       850        860        870        880        890        900 
SECNSTRSLL RSDSDEIVVY EMPVSPVEAP PLSPCTHNPL VNVRVERFKR DPNQSLTPTH 

       910        920        930        940        950        960 
VTLTTPSQPS SHRRTPSDGA LKPETLLASR SPSSNGLSPS PGAGMLKTPS PSRDPGEFPR 

       970        980        990       1000       1010       1020 
LPDPNVVFPP TPRRWNTQQD STLERPKTLE FLPRPRPSAN RQRLDPWWFV SPSHARSTSP 

      1030       1040       1050       1060       1070       1080 
ANSSSTETPS NLDSCFASSS STVEERPGLP ALLPFQAGPL PPTERTLLDL DAEGQSQDST 

      1090       1100 
VPLCRAELNT HRPAPYEIQQ EFWS 

« Hide

Isoform 2 [UniParc].

Checksum: 608E5BDC00DC09B8
Show »

FASTA1,118123,373

References

« Hide 'large scale' references
[1]"Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop."
Durkin J.T., Holskin B.P., Kopec K.K., Reed M.S., Spais C.M., Steffy B.M., Gessner G., Angeles T.S., Pohl J., Ator M.A., Meyer S.L.
Biochemistry 43:16348-16355(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, ENZYME REGULATION, PHOSPHORYLATION AT THR-304; THR-305; SER-308 AND THR-312, MUTAGENESIS OF LYS-171; THR-304; THR-305; SER-308 AND THR-312.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[3]"cDNA sequence and gene organisation of mixed lineage kinase 1."
McNee J.J., Dower S.K., Guesdon F.
Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 53-1104 (ISOFORM 2).
[4]"Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine-zipper domains."
Dorow D.S., Devereux L., Dietzsch E., de Kretser T.
Eur. J. Biochem. 213:701-710(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 142-535, TISSUE SPECIFICITY.
Tissue: Colon epithelium.
[5]"Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family."
Maroney A.C., Finn J.P., Connors T.J., Durkin J.T., Angeles T., Gessner G., Xu Z., Meyer S.L., Savage M.J., Greene L.A., Scott R.W., Vaught J.L.
J. Biol. Chem. 276:25302-25308(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, PHOSPHORYLATION OF MAP2K4/MKK4.
[6]"The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis."
Xu Z., Maroney A.C., Dobrzanski P., Kukekov N.V., Greene L.A.
Mol. Cell. Biol. 21:4713-4724(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN THE APOPTOSIS PATHWAY.
[7]"Mixed lineage kinase activity of indolocarbazole analogues."
Murakata C., Kaneko M., Gessner G., Angeles T.S., Ator M.A., O'Kane T.M., McKenna B.A., Thomas B.A., Mathiasen J.R., Saporito M.S., Bozyczko-Coyne D., Hudkins R.L.
Bioorg. Med. Chem. Lett. 12:147-150(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION.
[8]"Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues."
Chen J., Guo L., Peiffer D.A., Zhou L., Chan O.T., Bibikova M., Wickham-Garcia E., Lu S.H., Zhan Q., Wang-Rodriguez J., Jiang W., Fan J.B.
Int. J. Cancer 122:2249-2254(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE ROLE IN ESOPHAGEAL CANCER.
[9]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models."
Hudkins R.L., Diebold J.L., Tao M., Josef K.A., Park C.H., Angeles T.S., Aimone L.D., Husten J., Ator M.A., Meyer S.L., Holskin B.P., Durkin J.T., Fedorov A.A., Fedorov E.V., Almo S.C., Mathiasen J.R., Bozyczko-Coyne D., Saporito M.S., Scott R.W., Mallamo J.P.
J. Med. Chem. 51:5680-5689(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 136-406.
[11]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-246; CYS-467; GLN-497 AND CYS-646.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY327900 mRNA. Translation: AAQ23054.1.
BC111407 mRNA. Translation: AAI11408.1. Different initiation.
BC133706 mRNA. Translation: AAI33707.1.
AF251442 mRNA. Translation: AAG44591.1.
PIRJU0229. S32467.
RefSeqNP_001271159.1. NM_001284230.1.
NP_149132.2. NM_033141.3.
UniGeneHs.445496.
Hs.593542.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3DTCX-ray2.60A136-406[»]
ProteinModelPortalP80192.
SMRP80192. Positions 55-441.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110439. 1 interaction.
IntActP80192. 1 interaction.
STRING9606.ENSP00000005198.

Chemistry

BindingDBP80192.
ChEMBLCHEMBL2872.
GuidetoPHARMACOLOGY2084.

PTM databases

PhosphoSiteP80192.

Polymorphism databases

DMDM116242625.

Proteomic databases

PaxDbP80192.
PRIDEP80192.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000554752; ENSP00000451612; ENSG00000006432. [P80192-1]
ENST00000555993; ENSP00000451263; ENSG00000006432. [P80192-4]
GeneID4293.
KEGGhsa:4293.
UCSCuc001xml.3. human. [P80192-4]
uc001xmm.3. human. [P80192-1]

Organism-specific databases

CTD4293.
GeneCardsGC14M071189.
H-InvDBHIX0011779.
HGNCHGNC:6861. MAP3K9.
HPAHPA000942.
MIM600136. gene.
neXtProtNX_P80192.
PharmGKBPA30607.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000060081.
HOVERGENHBG067662.
KOK04417.
OMAFKRDPNQ.
OrthoDBEOG7D85VN.
PhylomeDBP80192.
TreeFamTF105118.

Enzyme and pathway databases

SignaLinkP80192.

Gene expression databases

ArrayExpressP80192.
BgeeP80192.
CleanExHS_MAP3K9.
GenevestigatorP80192.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR016231. MAPKKK9/10/11.
IPR015785. MAPKKK_4/9/10/11.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR001452. SH3_domain.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PANTHERPTHR23257:SF87. PTHR23257:SF87. 1 hit.
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF000556. MAPKKK9_11. 1 hit.
PRINTSPR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTSM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP80192.
GeneWikiMAP3K9.
GenomeRNAi4293.
NextBio16897.
PROP80192.
SOURCESearch...

Entry information

Entry nameM3K9_HUMAN
AccessionPrimary (citable) accession number: P80192
Secondary accession number(s): A3KN85 expand/collapse secondary AC list , Q0D2G7, Q6EH31, Q9H2N5
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: October 17, 2006
Last modified: April 16, 2014
This is version 142 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM