Q12851 (M4K2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase kinase kinase kinase 2
EC=2.7.11.1

Alternative name(s):
B lymphocyte serine/threonine-protein kinase
Germinal center kinase
Short name=GC kinase
MAPK/ERK kinase kinase kinase 2
Short name=MEK kinase kinase 2
Short name=MEKKK 2
Rab8-interacting protein

Gene names

Name:	MAP4K2
Synonyms:	GCK, RAB8IP

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	820 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extend of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.7
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.2
Cofactor	Magnesium. Ref.2
Enzyme regulation	The tumor necrosis factor (TNF), as well as endotoxins and proinflammatory stimuli such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan (PGN), flagellin, or lipid A activate MAP4K2 by promoting its autophosphorylation. Ref.3 Ref.6
Subunit structure	Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with RAB8A By similarity. Ref.4 Ref.5 Ref.6 Ref.7
Subcellular location	Cytoplasm By similarity. Basolateral cell membrane; Peripheral membrane protein By similarity. Golgi apparatus membrane; Peripheral membrane protein By similarity.
Tissue specificity	Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined. Ref.2
Domain	The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome. Ref.2
Post-translational modification	Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK. Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or proinflammatory stimuli. Autophosphorylation leads to activation. Ref.4
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.
Sequence caution	The sequence AAA20968.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

Ontologies

Keywords
Biological process	Immunity Innate immunity Stress response
Cellular component	Cell membrane Cytoplasm Golgi apparatus Membrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of JUN kinase activity Inferred from direct assay Ref.7. Source: UniProtKB immune response Traceable author statement Ref.2. Source: ProtInc innate immune response Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of JNK cascade Inferred from direct assay Ref.7. Source: UniProtKB vesicle targeting Non-traceable author statement. Source: UniProtKB
Cellular_component	Golgi membrane Traceable author statement PubMed 8643544. Source: ProtInc basolateral plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from direct assay Ref.5. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.5. Source: UniProtKB small GTPase regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MAP3K1	Q13233	2	EBI-49783,EBI-49776

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 820	820	Mitogen-activated protein kinase kinase kinase kinase 2		PRO_0000086275
Regions
	Domain	16 – 273	258	Protein kinase
	Domain	482 – 793	312	CNH
	Nucleotide binding	22 – 30	9	ATP By similarity
	Region	294 – 314	21	PEST1
	Region	344 – 360	17	PEST2
	Region	405 – 448	44	PEST3
Sites
	Active site	136	1	Proton acceptor By similarity
	Binding site	45	1	ATP By similarity
Amino acid modifications
	Modified residue	394	1	Phosphoserine Ref.10 Ref.11 Ref.12
Experimental info
	Sequence conflict	120	1	A → R in AAA20968. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q12851 [UniParc]. Last modified November 25, 2008. Version 2. Checksum: A59C1E99BFFAEF41	FASTA	820	91,556
	10 20 30 40 50 60 MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD PGDDISSLQQ 70 80 90 100 110 120 EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE IYHATGPLEE RQIAYVCREA 130 140 150 160 170 180 LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV KLADFGVSGE LTASVAKRRS FIGTPYWMAP 190 200 210 220 230 240 EVAAVERKGG YNELCDVWAL GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT 250 260 270 280 290 300 RWTQNFHHFL KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE 310 320 330 340 350 360 DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG 370 380 390 400 410 420 KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG TIKRAPFLGP LPTDPPAEEP 430 440 450 460 470 480 LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ REDPERSSCH GLPPTPKVHM GACFSKVFNG 490 500 510 520 530 540 CPLRIHAAVT WIHPVTRDQF LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL 550 560 570 580 590 600 LSLSGKSTHI WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ 610 620 630 640 650 660 CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM LEPLVLDGKE 670 680 690 700 710 720 LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI PGSAQQVIQV DRDTILVSFE 730 740 750 760 770 780 RCVRIVNMQG EPTATLAPEL TFDFPIETVV CLQDSVLAFW SHGMQGRSLD TNEVTQEITD 790 800 810 820 ETRIFRVLGA HRDIILESIP TDNPEAHSNL YILTGHQSTY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	"Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center." Katz P., Whalen G., Kehrl J.H. J. Biol. Chem. 269:16802-16809(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-820, FUNCTION, DOMAIN, TISSUE SPECIFICITY. Tissue: Tonsil.
[3]	"Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase." Pombo C.M., Kehrl J.H., Sanchez I., Katz P., Avruch J., Zon L.I., Woodgett J.R., Force T., Kyriakis J.M. Nature 377:750-754(1995) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION.
[4]	"Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38." Yuasa T., Ohno S., Kehrl J.H., Kyriakis J.M. J. Biol. Chem. 273:22681-22692(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, AUTOPHOSPHORYLATION, INTERACTION WITH MAP3K1/MEKK1 AND TRAF2.
[5]	"Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2." Chadee D.N., Yuasa T., Kyriakis J.M. Mol. Cell. Biol. 22:737-749(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TRAF2 AND MAP3K1.
[6]	"Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization." Zhong J., Kyriakis J.M. Mol. Cell. Biol. 24:9165-9175(2004) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, FUNCTION, UBIQUITINATION, INTERACTION WITH TRAF6.
[7]	"Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release." Zhong J., Kyriakis J.M. J. Biol. Chem. 282:24246-24254(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MAP3K11/MLK3.
[8]	"Signaling by the germinal center kinase family of protein kinases." Kyriakis J.M. J. Biol. Chem. 274:5259-5262(1999) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[9]	"The Ste20 group kinases as regulators of MAP kinase cascades." Dan I., Watanabe N.M., Kusumi A. Trends Cell Biol. 11:220-230(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"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-394, MASS SPECTROMETRY.
[12]	"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-394, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AP001462 Genomic DNA. No translation available. U07349 mRNA. Translation: AAA20968.1. Sequence problems.
IPI	IPI00149094.
PIR	A53714.
RefSeq	NP_004570.2. NM_004579.3.
UniGene	Hs.534341.
3D structure databases
ProteinModelPortal	Q12851.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q12851. 4 interactions.
STRING	9606.ENSP00000294066.
PTM databases
PhosphoSite	Q12851.
Polymorphism databases
DMDM	215274019.
Proteomic databases
PaxDb	Q12851.
PRIDE	Q12851.
Protocols and materials databases
DNASU	5871.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000294066; ENSP00000294066; ENSG00000168067.
GeneID	5871.
KEGG	hsa:5871.
UCSC	uc001obh.3. human.
Organism-specific databases
CTD	5871.
GeneCards	GC11M064556.
H-InvDB	HIX0026186.
HGNC	HGNC:6864. MAP4K2.
HPA	HPA007330.
MIM	603166. gene.
neXtProt	NX_Q12851.
PharmGKB	PA30610.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000230824.
HOVERGEN	HBG036702.
InParanoid	Q12851.
KO	K04414.
OMA	PGLFEQR.
OrthoDB	EOG4V6ZG4.
PhylomeDB	Q12851.
Enzyme and pathway databases
Pathway_Interaction_DB	tnfpathway. TNF receptor signaling pathway.
Gene expression databases
ArrayExpress	Q12851.
Bgee	Q12851.
CleanEx	HS_GCK. HS_MAP4K2.
Genevestigator	Q12851.
GermOnline	ENSG00000168067. 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	Q12851.
ChEMBL	CHEMBL5330.
GenomeRNAi	5871.
NextBio	22804.
SOURCE	Search...

Entry information

Entry name

M4K2_HUMAN

Accession

Primary (citable) accession number: Q12851

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 28, 2003
Last sequence update:	November 25, 2008
Last modified:	May 1, 2013
This is version 125 of the entry and version 2 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.