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Protein

Mitogen-activated protein kinase kinase kinase kinase 1

Gene

MAP4K1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei46 – 461ATPPROSITE-ProRule annotation
Active sitei137 – 1371Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi23 – 319ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • MAP kinase kinase kinase kinase activity Source: UniProtKB
  • protein kinase activity Source: ProtInc
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • activation of JUN kinase activity Source: ProtInc
  • activation of MAPKKK activity Source: UniProtKB
  • cell proliferation Source: UniProtKB
  • intracellular signal transduction Source: UniProtKB
  • peptidyl-serine phosphorylation Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • protein phosphorylation Source: UniProtKB
  • response to stress Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

SignaLinkiQ92918.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase kinase kinase kinase 1 (EC:2.7.11.1)
Alternative name(s):
Hematopoietic progenitor kinase
MAPK/ERK kinase kinase kinase 1
Short name:
MEK kinase kinase 1
Short name:
MEKKK 1
Gene namesi
Name:MAP4K1
Synonyms:HPK1
OrganismiHomo sapiens (Human)Imported
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:6863. MAP4K1.

Subcellular locationi

GO - Cellular componenti

  • intracellular Source: GOC
  • membrane Source: UniProtKB
Complete GO annotation...

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi355 – 3551T → A: Retains kinase activity. Not degraded by the Cul7-RING ubiquitin-protein ligase complex containing FBXW8. 1 Publication

Organism-specific databases

PharmGKBiPA30609.

Polymorphism and mutation databases

DMDMi29427916.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 833833Mitogen-activated protein kinase kinase kinase kinase 1PRO_0000086273Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei165 – 1651Phosphothreonine; by autocatalysis1 Publication
Modified residuei171 – 1711Phosphoserine; by autocatalysis1 Publication
Modified residuei175 – 1751Phosphothreonine; by autocatalysis1 Publication
Modified residuei355 – 3551Phosphothreonine; by autocatalysis1 Publication
Modified residuei405 – 4051Phosphoserine1 Publication
Modified residuei407 – 4071Phosphoserine1 Publication
Modified residuei413 – 4131Phosphoserine1 Publication
Modified residuei421 – 4211Phosphoserine2 Publications
Modified residuei586 – 5861Phosphoserine1 Publication

Post-translational modificationi

Autophosphorylates: phosphorylation promotes ubiquitination by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex, leading to its degradation by the proteasome.1 Publication
Ubiquitinated by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex following autophosphorylation, leading to its degradation by the proteasome.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ92918.
PaxDbiQ92918.
PRIDEiQ92918.

PTM databases

PhosphoSiteiQ92918.

Miscellaneous databases

PMAP-CutDBQ92918.

Expressioni

Tissue specificityi

Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine.1 Publication

Gene expression databases

BgeeiQ92918.
CleanExiHS_MAP4K1.
ExpressionAtlasiQ92918. baseline and differential.
GenevisibleiQ92918. HS.

Organism-specific databases

HPAiCAB007754.
HPA007419.

Interactioni

Subunit structurei

Interacts with MAP3K1. Interacts with FBXW8.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ABL1P005193EBI-881,EBI-375543
CRKP461083EBI-881,EBI-886
CRKLP461095EBI-881,EBI-910
FYNP062412EBI-881,EBI-515315
GRB2P629938EBI-881,EBI-401755
NCK1P163334EBI-881,EBI-389883
PIK3R1P279862EBI-881,EBI-79464
PLCG1P191746EBI-881,EBI-79387

Protein-protein interaction databases

BioGridi116354. 24 interactions.
DIPiDIP-31019N.
IntActiQ92918. 17 interactions.
MINTiMINT-1176198.
STRINGi9606.ENSP00000380066.

Structurei

3D structure databases

ProteinModelPortaliQ92918.
SMRiQ92918. Positions 1-331.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini17 – 274258Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini495 – 800306CNHPROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 CNH domain.PROSITE-ProRule annotationCurated
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124019.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ92918.
KOiK04408.
OMAiEMSTEHR.
OrthoDBiEOG7WX07M.
PhylomeDBiQ92918.
TreeFamiTF105121.

Family and domain databases

InterProiIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038172. MAPKKKK. 1 hit.
SMARTiSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q92918-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MDVVDPDIFN RDPRDHYDLL QRLGGGTYGE VFKARDKVSG DLVALKMVKM
60 70 80 90 100
EPDDDVSTLQ KEILILKTCR HANIVAYHGS YLWLQKLWIC MEFCGAGSLQ
110 120 130 140 150
DIYQVTGSLS ELQISYVCRE VLQGLAYLHS QKKIHRDIKG ANILINDAGE
160 170 180 190 200
VRLADFGISA QIGATLARRL SFIGTPYWMA PEVAAVALKG GYNELCDIWS
210 220 230 240 250
LGITAIELAE LQPPLFDVHP LRVLFLMTKS GYQPPRLKEK GKWSAAFHNF
260 270 280 290 300
IKVTLTKSPK KRPSATKMLS HQLVSQPGLN RGLILDLLDK LKNPGKGPSI
310 320 330 340 350
GDIEDEEPEL PPAIPRRIRS THRSSSLGIP DADCCRRHME FRKLRGMETR
360 370 380 390 400
PPANTARLQP PRDLRSSSPR KQLSESSDDD YDDVDIPTPA EDTPPPLPPK
410 420 430 440 450
PKFRSPSDEG PGSMGDDGQL SPGVLVRCAS GPPPNSPRPG PPPSTSSPHL
460 470 480 490 500
TAHSEPSLWN PPSRELDKPP LLPPKKEKMK RKGCALLVKL FNGCPLRIHS
510 520 530 540 550
TAAWTHPSTK DQHLLLGAEE GIFILNRNDQ EATLEMLFPS RTTWVYSINN
560 570 580 590 600
VLMSLSGKTP HLYSHSILGL LERKETRAGN PIAHISPHRL LARKNMVSTK
610 620 630 640 650
IQDTKGCRAC CVAEGASSGG PFLCGALETS VVLLQWYQPM NKFLLVRQVL
660 670 680 690 700
FPLPTPLSVF ALLTGPGSEL PAVCIGVSPG RPGKSVLFHT VRFGALSCWL
710 720 730 740 750
GEMSTEHRGP VQVTQVEEDM VMVLMDGSVK LVTPEGSPVR GLRTPEIPMT
760 770 780 790 800
EAVEAVAMVG GQLQAFWKHG VQVWALGSDQ LLQELRDPTL TFRLLGSPRL
810 820 830
ECSGTISPHC NLLLPGSSNS PASASRVAGI TGL
Length:833
Mass (Da):91,296
Last modified:February 1, 1997 - v1
Checksum:i3C98CF01BE42E151
GO
Isoform 2 (identifier: Q92918-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     800-833: LECSGTISPHCNLLLPGSSNSPASASRVAGITGL → PVVVETRPVDDPTAPSNLYIQE

Show »
Length:821
Mass (Da):90,425
Checksum:iA7CBFE3B39D1C66A
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti312 – 3121P → T.1 Publication
Corresponds to variant rs55924696 [ dbSNP | Ensembl ].
VAR_040739
Natural varianti351 – 3511P → S.1 Publication
Corresponds to variant rs34591617 [ dbSNP | Ensembl ].
VAR_040740
Natural varianti361 – 3611P → L.1 Publication
Corresponds to variant rs56060067 [ dbSNP | Ensembl ].
VAR_040741
Natural varianti737 – 7371S → F in a metastatic melanoma sample; somatic mutation. 1 Publication
VAR_040742
Natural varianti811 – 8111N → S.
Corresponds to variant rs12975825 [ dbSNP | Ensembl ].
VAR_051643

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei800 – 83334LECSG…GITGL → PVVVETRPVDDPTAPSNLYI QE in isoform 2. CuratedVSP_040340Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66464 mRNA. Translation: AAB97983.1.
AC005933 Genomic DNA. No translation available.
AC008649 Genomic DNA. No translation available.
CCDSiCCDS42564.1. [Q92918-2]
CCDS59385.1. [Q92918-1]
RefSeqiNP_001036065.1. NM_001042600.2. [Q92918-2]
NP_009112.1. NM_007181.5. [Q92918-1]
UniGeneiHs.95424.

Genome annotation databases

EnsembliENST00000396857; ENSP00000380066; ENSG00000104814. [Q92918-2]
ENST00000591517; ENSP00000465039; ENSG00000104814.
GeneIDi11184.
KEGGihsa:11184.
UCSCiuc002oix.1. human. [Q92918-1]
uc002oiy.1. human. [Q92918-2]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66464 mRNA. Translation: AAB97983.1.
AC005933 Genomic DNA. No translation available.
AC008649 Genomic DNA. No translation available.
CCDSiCCDS42564.1. [Q92918-2]
CCDS59385.1. [Q92918-1]
RefSeqiNP_001036065.1. NM_001042600.2. [Q92918-2]
NP_009112.1. NM_007181.5. [Q92918-1]
UniGeneiHs.95424.

3D structure databases

ProteinModelPortaliQ92918.
SMRiQ92918. Positions 1-331.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116354. 24 interactions.
DIPiDIP-31019N.
IntActiQ92918. 17 interactions.
MINTiMINT-1176198.
STRINGi9606.ENSP00000380066.

Chemistry

BindingDBiQ92918.
ChEMBLiCHEMBL5749.
GuidetoPHARMACOLOGYi2085.

PTM databases

PhosphoSiteiQ92918.

Polymorphism and mutation databases

DMDMi29427916.

Proteomic databases

MaxQBiQ92918.
PaxDbiQ92918.
PRIDEiQ92918.

Protocols and materials databases

DNASUi11184.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000396857; ENSP00000380066; ENSG00000104814. [Q92918-2]
ENST00000591517; ENSP00000465039; ENSG00000104814.
GeneIDi11184.
KEGGihsa:11184.
UCSCiuc002oix.1. human. [Q92918-1]
uc002oiy.1. human. [Q92918-2]

Organism-specific databases

CTDi11184.
GeneCardsiGC19M039078.
HGNCiHGNC:6863. MAP4K1.
HPAiCAB007754.
HPA007419.
MIMi601983. gene.
neXtProtiNX_Q92918.
PharmGKBiPA30609.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124019.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ92918.
KOiK04408.
OMAiEMSTEHR.
OrthoDBiEOG7WX07M.
PhylomeDBiQ92918.
TreeFamiTF105121.

Enzyme and pathway databases

SignaLinkiQ92918.

Miscellaneous databases

GeneWikiiMAP4K1.
GenomeRNAii11184.
NextBioi42561.
PMAP-CutDBQ92918.
PROiQ92918.
SOURCEiSearch...

Gene expression databases

BgeeiQ92918.
CleanExiHS_MAP4K1.
ExpressionAtlasiQ92918. baseline and differential.
GenevisibleiQ92918. HS.

Family and domain databases

InterProiIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038172. MAPKKKK. 1 hit.
SMARTiSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade."
    Hu M.C.-T., Qiu W.R., Wang X., Meyer C.F., Tan T.-H.
    Genes Dev. 10:2251-2264(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH MAP3K1.
    Tissue: Fetal liver.
  2. "The DNA sequence and biology of human chromosome 19."
    Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V.
    , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
    Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421 AND SER-586, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  4. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
    Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
    Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-405; SER-407; SER-413 AND SER-421, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Leukemic T-cell.
  5. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  6. "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.
    , 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] THR-312; SER-351; LEU-361 AND PHE-737.
  7. "The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1."
    Wang H., Chen Y., Lin P., Li L., Zhou G., Liu G., Logsdon C., Jin J., Abbruzzese J.L., Tan T.H., Wang H.
    J. Biol. Chem. 289:4009-4017(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PHOSPHORYLATION AT THR-165; SER-171; THR-175 AND THR-355, UBIQUITINATION, MUTAGENESIS OF THR-355, INTERACTION WITH FBXW8.

Entry informationi

Entry nameiM4K1_HUMAN
AccessioniPrimary (citable) accession number: Q92918
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 28, 2003
Last sequence update: February 1, 1997
Last modified: July 22, 2015
This is version 147 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.