Q8IVH8 (M4K3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase kinase kinase kinase 3
EC=2.7.11.1

Alternative name(s):
Germinal center kinase-related protein kinase
Short name=GLK
MAPK/ERK kinase kinase kinase 3
Short name=MEK kinase kinase 3
Short name=MEKKK 3

Gene names

Name:	MAP4K3
Synonyms:	RAB8IPL1

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	894 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. Ref.1
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1
Cofactor	Magnesium. Ref.1
Subunit structure	Interacts with SH3GL2. Interaction appears to regulate MAP4K3-mediated JNK activation By similarity. UniProtKB Q924I2
Tissue specificity	Ubiquitously expressed in all tissues examined, with high levels in heart, brain, placenta, skeletal muscle, kidney and pancreas and lower levels in lung and liver. 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	JNK cascade Traceable author statement Ref.1. Source: ProtInc
Molecular_function	ATP binding Inferred from direct assay Ref.1. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.1. Source: UniProtKB small GTPase regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GRB2	P62993	2	EBI-1758170,EBI-401755
LCP2	Q13094	5	EBI-1758170,EBI-346946
PRKCQ	Q04759	4	EBI-1758170,EBI-374762
Prkcq	Q02111	4	EBI-1758170,EBI-2639157	From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 Ref.1 (identifier: Q8IVH8-1)

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.

Note: No experimental confirmation available.

Isoform 2 Ref.1 (identifier: Q8IVH8-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-12: MNPGFDLSRRNP → MA

Isoform 3 Ref.1 (identifier: Q8IVH8-3)

The sequence of this isoform differs from the canonical sequence as follows:
     352-372: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 894	894	Mitogen-activated protein kinase kinase kinase kinase 3		PRO_0000086277
Regions
	Domain	16 – 273	258	Protein kinase
	Domain	556 – 867	312	CNH
	Nucleotide binding	22 – 30	9	ATP By similarity UniProtKB O00506
Sites
	Active site	136	1	Proton acceptor By similarity UniProtKB O00506
	Binding site	45	1	ATP By similarity
	Binding site	48	1	ATP Ref.1
Amino acid modifications
	Modified residue	398	1	Phosphoserine Ref.6
Natural variations
	Alternative sequence	1 – 12	12	MNPGF…SRRNP → MA in isoform 2. Ref.1		VSP_007052
	Alternative sequence	352 – 372	21	Missing in isoform 3.		VSP_007053
	Natural variant	200	1	V → L. Ref.7 Corresponds to variant rs35957290 [ dbSNP | Ensembl ].		VAR_040743
	Natural variant	424	1	H → Q. Ref.7 Corresponds to variant rs56317466 [ dbSNP | Ensembl ].		VAR_040744
	Natural variant	669	1	T → S in a lung squamous cell carcinoma sample; somatic mutation. Ref.7		VAR_040745
Experimental info
	Mutagenesis	48	1	K → E: Loss of kinase activity and ability to activate JNK family. Ref.1
	Sequence conflict	392	1	N → D in AAC15472. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2003. Version 1. Checksum: 6EB77BBB34E5B733	FASTA	894	101,316
	10 20 30 40 50 60 MNPGFDLSRR NPQEDFELIQ RIGSGTYGDV YKARNVNTGE LAAIKVIKLE PGEDFAVVQQ 70 80 90 100 110 120 EIIMMKDCKH PNIVAYFGSY LRRDKLWICM EFCGGGSLQD IYHVTGPLSE LQIAYVSRET 130 140 150 160 170 180 LQGLYYLHSK GKMHRDIKGA NILLTDNGHV KLADFGVSAQ ITATIAKRKS FIGTPYWMAP 190 200 210 220 230 240 EVAAVERKGG YNQLCDLWAV GITAIELAEL QPPMFDLHPM RALFLMTKSN FQPPKLKDKM 250 260 270 280 290 300 KWSNSFHHFV KMALTKNPKK RPTAEKLLQH PFVTQHLTRS LAIELLDKVN NPDHSTYHDF 310 320 330 340 350 360 DDDDPEPLVA VPHRIHSTSR NVREEKTRSE ITFGQVKFDP PLRKETEPHH ELPDSDGFLD 370 380 390 400 410 420 SSEEIYYTAR SNLDLQLEYG QGHQGGYFLG ANKSLLKSVE EELHQRGHVA HLEDDEGDDD 430 440 450 460 470 480 ESKHSTLKAK IPPPLPPKPK SIFIPQEMHS TEDENQGTIK RCPMSGSPAK PSQVPPRPPP 490 500 510 520 530 540 PRLPPHKPVA LGNGMSSFQL NGERDGSLCQ QQNEHRGTNL SRKEKKDVPK PISNGLPPTP 550 560 570 580 590 600 KVHMGACFSK VFNGCPLKIH CASSWINPDT RDQYLIFGAE EGIYTLNLNE LHETSMEQLF 610 620 630 640 650 660 PRRCTWLYVM NNCLLSISGK ASQLYSHNLP GLFDYARQMQ KLPVAIPAHK LPDRILPRKF 670 680 690 700 710 720 SVSAKIPETK WCQKCCVVRN PYTGHKYLCG ALQTSIVLLE WVEPMQKFML IKHIDFPIPC 730 740 750 760 770 780 PLRMFEMLVV PEQEYPLVCV GVSRGRDFNQ VVRFETVNPN STSSWFTESD TPQTNVTHVT 790 800 810 820 830 840 QLERDTILVC LDCCIKIVNL QGRLKSSRKL SSELTFDFQI ESIVCLQDSV LAFWKHGMQG 850 860 870 880 890 RSFRSNEVTQ EISDSTRIFR LLGSDRVVVL ESRPTDNPTA NSNLYILAGH ENSY
	Isoform 2 [UniParc]. Checksum: 14839222F5360166	FASTA	884	100,133
	10 20 30 40 50 60 MAQEDFELIQ RIGSGTYGDV YKARNVNTGE LAAIKVIKLE PGEDFAVVQQ EIIMMKDCKH 70 80 90 100 110 120 PNIVAYFGSY LRRDKLWICM EFCGGGSLQD IYHVTGPLSE LQIAYVSRET LQGLYYLHSK 130 140 150 160 170 180 GKMHRDIKGA NILLTDNGHV KLADFGVSAQ ITATIAKRKS FIGTPYWMAP EVAAVERKGG 190 200 210 220 230 240 YNQLCDLWAV GITAIELAEL QPPMFDLHPM RALFLMTKSN FQPPKLKDKM KWSNSFHHFV 250 260 270 280 290 300 KMALTKNPKK RPTAEKLLQH PFVTQHLTRS LAIELLDKVN NPDHSTYHDF DDDDPEPLVA 310 320 330 340 350 360 VPHRIHSTSR NVREEKTRSE ITFGQVKFDP PLRKETEPHH ELPDSDGFLD SSEEIYYTAR 370 380 390 400 410 420 SNLDLQLEYG QGHQGGYFLG ANKSLLKSVE EELHQRGHVA HLEDDEGDDD ESKHSTLKAK 430 440 450 460 470 480 IPPPLPPKPK SIFIPQEMHS TEDENQGTIK RCPMSGSPAK PSQVPPRPPP PRLPPHKPVA 490 500 510 520 530 540 LGNGMSSFQL NGERDGSLCQ QQNEHRGTNL SRKEKKDVPK PISNGLPPTP KVHMGACFSK 550 560 570 580 590 600 VFNGCPLKIH CASSWINPDT RDQYLIFGAE EGIYTLNLNE LHETSMEQLF PRRCTWLYVM 610 620 630 640 650 660 NNCLLSISGK ASQLYSHNLP GLFDYARQMQ KLPVAIPAHK LPDRILPRKF SVSAKIPETK 670 680 690 700 710 720 WCQKCCVVRN PYTGHKYLCG ALQTSIVLLE WVEPMQKFML IKHIDFPIPC PLRMFEMLVV 730 740 750 760 770 780 PEQEYPLVCV GVSRGRDFNQ VVRFETVNPN STSSWFTESD TPQTNVTHVT QLERDTILVC 790 800 810 820 830 840 LDCCIKIVNL QGRLKSSRKL SSELTFDFQI ESIVCLQDSV LAFWKHGMQG RSFRSNEVTQ 850 860 870 880 EISDSTRIFR LLGSDRVVVL ESRPTDNPTA NSNLYILAGH ENSY
	Isoform 3 [UniParc]. Checksum: 0C7D648387CFFE0C	FASTA	873	98,954
	10 20 30 40 50 60 MNPGFDLSRR NPQEDFELIQ RIGSGTYGDV YKARNVNTGE LAAIKVIKLE PGEDFAVVQQ 70 80 90 100 110 120 EIIMMKDCKH PNIVAYFGSY LRRDKLWICM EFCGGGSLQD IYHVTGPLSE LQIAYVSRET 130 140 150 160 170 180 LQGLYYLHSK GKMHRDIKGA NILLTDNGHV KLADFGVSAQ ITATIAKRKS FIGTPYWMAP 190 200 210 220 230 240 EVAAVERKGG YNQLCDLWAV GITAIELAEL QPPMFDLHPM RALFLMTKSN FQPPKLKDKM 250 260 270 280 290 300 KWSNSFHHFV KMALTKNPKK RPTAEKLLQH PFVTQHLTRS LAIELLDKVN NPDHSTYHDF 310 320 330 340 350 360 DDDDPEPLVA VPHRIHSTSR NVREEKTRSE ITFGQVKFDP PLRKETEPHH ELDLQLEYGQ 370 380 390 400 410 420 GHQGGYFLGA NKSLLKSVEE ELHQRGHVAH LEDDEGDDDE SKHSTLKAKI PPPLPPKPKS 430 440 450 460 470 480 IFIPQEMHST EDENQGTIKR CPMSGSPAKP SQVPPRPPPP RLPPHKPVAL GNGMSSFQLN 490 500 510 520 530 540 GERDGSLCQQ QNEHRGTNLS RKEKKDVPKP ISNGLPPTPK VHMGACFSKV FNGCPLKIHC 550 560 570 580 590 600 ASSWINPDTR DQYLIFGAEE GIYTLNLNEL HETSMEQLFP RRCTWLYVMN NCLLSISGKA 610 620 630 640 650 660 SQLYSHNLPG LFDYARQMQK LPVAIPAHKL PDRILPRKFS VSAKIPETKW CQKCCVVRNP 670 680 690 700 710 720 YTGHKYLCGA LQTSIVLLEW VEPMQKFMLI KHIDFPIPCP LRMFEMLVVP EQEYPLVCVG 730 740 750 760 770 780 VSRGRDFNQV VRFETVNPNS TSSWFTESDT PQTNVTHVTQ LERDTILVCL DCCIKIVNLQ 790 800 810 820 830 840 GRLKSSRKLS SELTFDFQIE SIVCLQDSVL AFWKHGMQGR SFRSNEVTQE ISDSTRIFRL 850 860 870 LGSDRVVVLE SRPTDNPTAN SNLYILAGHE NSY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase." Diener K., Wang X.S., Chen C., Meyer C.F., Keesler G., Zukowski M., Tan T.-H., Yao Z. Proc. Natl. Acad. Sci. U.S.A. 94:9687-9692(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-48. Tissue: Macrophage and Skeletal muscle.
[2]	"Physical/genetic map of the 2p22-2p21 region on chromosome 2." Gorry M.C., Zhang Y., Marks J.J., Suppe B., Hart S., Cortelli J., Pallos D., Hart T.C. Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 3).
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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 3). Tissue: Testis.
[5]	Edwards J., Wohldmann P., Hawkins M., Harkins R. Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE OF 1-712 (ISOFORM 1).
[6]	"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-398, MASS SPECTROMETRY.
[7]	"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] LEU-200; GLN-424 AND SER-669.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF000145 mRNA. Translation: AAC15472.1. AF445413 , AF445385, AF445386, AF445387, AF445388, AF445390, AF445391, AF445392, AF445393, AF445394, AF445395, AF445396, AF445397, AF445398, AF445399, AF445400, AF445401, AF445402, AF445403, AF445404, AF445405, AF445406, AF445407, AF445408, AF445409, AF445410, AF445411, AF445412 Genomic DNA. Translation: AAN75849.1. AF445413 , AF445385, AF445386, AF445387, AF445388, AF445390, AF445391, AF445392, AF445393, AF445394, AF445395, AF445397, AF445398, AF445399, AF445400, AF445401, AF445402, AF445403, AF445404, AF445405, AF445406, AF445407, AF445408, AF445409, AF445410, AF445411, AF445412 Genomic DNA. Translation: AAN75850.1. CH471053 Genomic DNA. Translation: EAX00346.1. BC071579 mRNA. Translation: AAH71579.1. AC007684 Genomic DNA. Translation: AAF19240.1.
IPI	IPI00217024. IPI00219509. IPI00219510.
RefSeq	NP_001257354.1. NM_001270425.1. NP_003609.2. NM_003618.3.
UniGene	Hs.655750.
3D structure databases
ProteinModelPortal	Q8IVH8.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-48924N.
IntAct	Q8IVH8. 10 interactions.
STRING	9606.ENSP00000263881.
PTM databases
PhosphoSite	Q8IVH8.
Polymorphism databases
DMDM	29427817.
Proteomic databases
PaxDb	Q8IVH8.
PRIDE	Q8IVH8.
Protocols and materials databases
DNASU	8491.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000263881; ENSP00000263881; ENSG00000011566. ENST00000341681; ENSP00000345434; ENSG00000011566.
GeneID	8491.
KEGG	hsa:8491.
UCSC	uc002rro.3. human. uc002rrp.3. human.
Organism-specific databases
CTD	8491.
GeneCards	GC02M039476.
H-InvDB	HIX0001996.
HGNC	HGNC:6865. MAP4K3.
HPA	HPA030380.
MIM	604921. gene.
neXtProt	NX_Q8IVH8.
PharmGKB	PA30611.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000230824.
HOVERGEN	HBG036702.
InParanoid	Q8IVH8.
KO	K04406.
OMA	FIPQETH.
OrthoDB	EOG4MGS6R.
PhylomeDB	Q8IVH8.
Enzyme and pathway databases
Pathway_Interaction_DB	tnfpathway. TNF receptor signaling pathway.
SignaLink	Q8IVH8.
Gene expression databases
ArrayExpress	Q8IVH8.
Bgee	Q8IVH8.
CleanEx	HS_MAP4K3.
Genevestigator	Q8IVH8.
GermOnline	ENSG00000011566. 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	Q8IVH8.
ChEMBL	CHEMBL5432.
ChiTaRS	MAP4K3. human.
GenomeRNAi	8491.
NextBio	31767.
SOURCE	Search...

Entry information

Entry name

M4K3_HUMAN

Accession

Primary (citable) accession number: Q8IVH8
Secondary accession number(s): Q6IQ39 , Q8IVH7, Q9UDM5, Q9Y6R5

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 28, 2003
Last sequence update:	March 1, 2003
Last modified:	May 29, 2013
This is version 106 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.