Q92918 (M4K1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	MAP4K1
Synonyms:	HPK1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	833 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.1
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1
Cofactor	Magnesium. Ref.1
Subunit structure	Interacts with MAP3K1. Ref.1
Tissue specificity	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. Ref.1
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. Contains 1 CNH domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of JUN kinase activity Traceable author statement Ref.1. Source: ProtInc peptidyl-serine phosphorylation Inferred from direct assay PubMed 11053428. Source: UniProtKB
Molecular_function	ATP binding Inferred from direct assay Ref.1. Source: UniProtKB MAP kinase kinase kinase kinase activity Inferred from direct assay PubMed 11053428. Source: UniProtKB small GTPase regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ABL1	P00519	2	EBI-881,EBI-375543
CRK	P46108	3	EBI-881,EBI-886
CRKL	P46109	5	EBI-881,EBI-910
FYN	P06241	2	EBI-881,EBI-515315
GRB2	P62993	2	EBI-881,EBI-401755
NCK1	P16333	2	EBI-881,EBI-389883
PIK3R1	P27986	2	EBI-881,EBI-79464
PLCG1	P19174	6	EBI-881,EBI-79387

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q92918-1)

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: Q92918-2)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 833	833	Mitogen-activated protein kinase kinase kinase kinase 1		PRO_0000086273
Regions
	Domain	17 – 274	258	Protein kinase
	Domain	495 – 800	306	CNH
	Nucleotide binding	23 – 31	9	ATP By similarity UniProtKB O00506
Sites
	Active site	137	1	Proton acceptor By similarity UniProtKB O00506
	Binding site	46	1	ATP By similarity UniProtKB P70218
Amino acid modifications
	Modified residue	405	1	Phosphoserine Ref.4
	Modified residue	407	1	Phosphoserine Ref.4
	Modified residue	413	1	Phosphoserine Ref.4
	Modified residue	421	1	Phosphoserine Ref.3 Ref.4
	Modified residue	586	1	Phosphoserine Ref.3
Natural variations
	Alternative sequence	800 – 833	34	LECSG…GITGL → PVVVETRPVDDPTAPSNLYI QE in isoform 2.		VSP_040340
	Natural variant	312	1	P → T. Ref.6 Corresponds to variant rs55924696 [ dbSNP | Ensembl ].		VAR_040739
	Natural variant	351	1	P → S. Ref.6 Corresponds to variant rs34591617 [ dbSNP | Ensembl ].		VAR_040740
	Natural variant	361	1	P → L. Ref.6 Corresponds to variant rs56060067 [ dbSNP | Ensembl ].		VAR_040741
	Natural variant	737	1	S → F in a metastatic melanoma sample; somatic mutation. Ref.6		VAR_040742
	Natural variant	811	1	N → S. Corresponds to variant rs12975825 [ dbSNP | Ensembl ].		VAR_051643

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: 3C98CF01BE42E151	FASTA	833	91,296
	10 20 30 40 50 60 MDVVDPDIFN RDPRDHYDLL QRLGGGTYGE VFKARDKVSG DLVALKMVKM EPDDDVSTLQ 70 80 90 100 110 120 KEILILKTCR HANIVAYHGS YLWLQKLWIC MEFCGAGSLQ DIYQVTGSLS ELQISYVCRE 130 140 150 160 170 180 VLQGLAYLHS QKKIHRDIKG ANILINDAGE VRLADFGISA QIGATLARRL SFIGTPYWMA 190 200 210 220 230 240 PEVAAVALKG GYNELCDIWS LGITAIELAE LQPPLFDVHP LRVLFLMTKS GYQPPRLKEK 250 260 270 280 290 300 GKWSAAFHNF IKVTLTKSPK KRPSATKMLS HQLVSQPGLN RGLILDLLDK LKNPGKGPSI 310 320 330 340 350 360 GDIEDEEPEL PPAIPRRIRS THRSSSLGIP DADCCRRHME FRKLRGMETR PPANTARLQP 370 380 390 400 410 420 PRDLRSSSPR KQLSESSDDD YDDVDIPTPA EDTPPPLPPK PKFRSPSDEG PGSMGDDGQL 430 440 450 460 470 480 SPGVLVRCAS GPPPNSPRPG PPPSTSSPHL TAHSEPSLWN PPSRELDKPP LLPPKKEKMK 490 500 510 520 530 540 RKGCALLVKL FNGCPLRIHS TAAWTHPSTK DQHLLLGAEE GIFILNRNDQ EATLEMLFPS 550 560 570 580 590 600 RTTWVYSINN VLMSLSGKTP HLYSHSILGL LERKETRAGN PIAHISPHRL LARKNMVSTK 610 620 630 640 650 660 IQDTKGCRAC CVAEGASSGG PFLCGALETS VVLLQWYQPM NKFLLVRQVL FPLPTPLSVF 670 680 690 700 710 720 ALLTGPGSEL PAVCIGVSPG RPGKSVLFHT VRFGALSCWL GEMSTEHRGP VQVTQVEEDM 730 740 750 760 770 780 VMVLMDGSVK LVTPEGSPVR GLRTPEIPMT EAVEAVAMVG GQLQAFWKHG VQVWALGSDQ 790 800 810 820 830 LLQELRDPTL TFRLLGSPRL ECSGTISPHC NLLLPGSSNS PASASRVAGI TGL
	Isoform 2 [UniParc]. Checksum: A7CBFE3B39D1C66A	FASTA	821	90,425
	10 20 30 40 50 60 MDVVDPDIFN RDPRDHYDLL QRLGGGTYGE VFKARDKVSG DLVALKMVKM EPDDDVSTLQ 70 80 90 100 110 120 KEILILKTCR HANIVAYHGS YLWLQKLWIC MEFCGAGSLQ DIYQVTGSLS ELQISYVCRE 130 140 150 160 170 180 VLQGLAYLHS QKKIHRDIKG ANILINDAGE VRLADFGISA QIGATLARRL SFIGTPYWMA 190 200 210 220 230 240 PEVAAVALKG GYNELCDIWS LGITAIELAE LQPPLFDVHP LRVLFLMTKS GYQPPRLKEK 250 260 270 280 290 300 GKWSAAFHNF IKVTLTKSPK KRPSATKMLS HQLVSQPGLN RGLILDLLDK LKNPGKGPSI 310 320 330 340 350 360 GDIEDEEPEL PPAIPRRIRS THRSSSLGIP DADCCRRHME FRKLRGMETR PPANTARLQP 370 380 390 400 410 420 PRDLRSSSPR KQLSESSDDD YDDVDIPTPA EDTPPPLPPK PKFRSPSDEG PGSMGDDGQL 430 440 450 460 470 480 SPGVLVRCAS GPPPNSPRPG PPPSTSSPHL TAHSEPSLWN PPSRELDKPP LLPPKKEKMK 490 500 510 520 530 540 RKGCALLVKL FNGCPLRIHS TAAWTHPSTK DQHLLLGAEE GIFILNRNDQ EATLEMLFPS 550 560 570 580 590 600 RTTWVYSINN VLMSLSGKTP HLYSHSILGL LERKETRAGN PIAHISPHRL LARKNMVSTK 610 620 630 640 650 660 IQDTKGCRAC CVAEGASSGG PFLCGALETS VVLLQWYQPM NKFLLVRQVL FPLPTPLSVF 670 680 690 700 710 720 ALLTGPGSEL PAVCIGVSPG RPGKSVLFHT VRFGALSCWL GEMSTEHRGP VQVTQVEEDM 730 740 750 760 770 780 VMVLMDGSVK LVTPEGSPVR GLRTPEIPMT EAVEAVAMVG GQLQAFWKHG VQVWALGSDQ 790 800 810 820 LLQELRDPTL TFRLLGSPRP VVVETRPVDD PTAPSNLYIQ E

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421 AND SER-586, MASS SPECTROMETRY.
[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, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[5]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U66464 mRNA. Translation: AAB97983.1. AC005933 Genomic DNA. No translation available. AC008649 Genomic DNA. No translation available.
IPI	IPI00020258. IPI00784270.
RefSeq	NP_001036065.1. NM_001042600.1. NP_009112.1. NM_007181.4.
UniGene	Hs.95424.
3D structure databases
ProteinModelPortal	Q92918.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-31019N.
IntAct	Q92918. 15 interactions.
MINT	MINT-1176198.
STRING	9606.ENSP00000380066.
PTM databases
PhosphoSite	Q92918.
Polymorphism databases
DMDM	29427916.
Proteomic databases
PaxDb	Q92918.
PRIDE	Q92918.
Protocols and materials databases
DNASU	11184.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000396857; ENSP00000380066; ENSG00000104814. ENST00000591517; ENSP00000465039; ENSG00000104814.
GeneID	11184.
KEGG	hsa:11184.
UCSC	uc002oix.1. human. uc002oiy.1. human.
Organism-specific databases
CTD	11184.
GeneCards	GC19M039078.
HGNC	HGNC:6863. MAP4K1.
HPA	CAB007754. HPA007419.
MIM	601983. gene.
neXtProt	NX_Q92918.
PharmGKB	PA30609.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000230824.
HOVERGEN	HBG036702.
InParanoid	Q92918.
KO	K04408.
OMA	KRKGCAL.
PhylomeDB	Q92918.
Enzyme and pathway databases
Pathway_Interaction_DB	bcr_5pathway. BCR signaling pathway. tcrjnkpathway. JNK signaling in the CD4+ TCR pathway. met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met). kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit). tcrpathway. TCR signaling in naive CD4+ T cells.
SignaLink	Q92918.
Gene expression databases
ArrayExpress	Q92918.
Bgee	Q92918.
CleanEx	HS_MAP4K1.
Genevestigator	Q92918.
GermOnline	ENSG00000104814. Homo sapiens.
Family and domain databases
InterPro	IPR001180. Citron. IPR011009. Kinase-like_dom. IPR021160. MAPKKKK. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. [Graphical view]
Pfam	PF00780. CNH. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF038172. MAPKKKK. 1 hit.
SMART	SM00036. CNH. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50219. CNH. 1 hit. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. False negative. [Graphical view]
ProtoNet	Search...
Other
BindingDB	Q92918.
ChEMBL	CHEMBL5749.
GenomeRNAi	11184.
NextBio	42561.
PMAP-CutDB	Q92918.
SOURCE	Search...

Entry information

Entry name

M4K1_HUMAN

Accession

Primary (citable) accession number: Q92918

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 28, 2003
Last sequence update:	February 1, 1997
Last modified:	May 29, 2013
This is version 125 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.