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Q61161 (M4K2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase kinase 2

EC=2.7.11.1
Alternative name(s):
Germinal center kinase
Short name=GCK
MAPK/ERK kinase kinase kinase 2
Short name=MEK kinase kinase 2
Short name=MEKKK 2
Rab8-interacting protein
Gene names
Name:Map4k2
Synonyms:Rab8ip
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length821 AA.
Sequence statusComplete.
Protein existenceEvidence 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.1 Ref.3

Catalytic activity

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

Cofactor

Magnesium. Ref.1

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.

Subunit structure

Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3 By similarity. Interacts with RAB8A. Ref.1

Subcellular location

Cytoplasm. Basolateral cell membrane; Peripheral membrane protein. Golgi apparatus membrane; Peripheral membrane protein Ref.1.

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.

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.

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
   Biological processImmunity
Innate immunity
Stress response
   Cellular componentCell membrane
Cytoplasm
Golgi apparatus
Membrane
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of JUN kinase activity

Inferred from electronic annotation. Source: Ensembl

activation of MAPKKK activity

Inferred from Biological aspect of Ancestor. Source: GOC

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

vesicle targeting

Inferred from direct assay Ref.1. Source: UniProtKB

   Cellular_componentGolgi membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

basolateral plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionATP binding

Inferred from sequence or structural similarity. Source: UniProtKB

MAP kinase kinase kinase kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

small GTPase regulator activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 821821Mitogen-activated protein kinase kinase kinase kinase 2
PRO_0000086276

Regions

Domain16 – 273258Protein kinase
Domain483 – 794312CNH
Nucleotide binding22 – 309ATP By similarity UniProtKB O00506
Region294 – 31421PEST1
Region344 – 36017PEST2
Region405 – 44945PEST3

Sites

Active site1361Proton acceptor By similarity UniProtKB O00506
Binding site451ATP By similarity UniProtKB O00506

Amino acid modifications

Modified residue3941Phosphoserine By similarity

Experimental info

Sequence conflict2231L → M in BAC34507. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q61161 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 2CCF750E45A53B05

FASTA82191,265
        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 RPTAERLLQH PFTTQHLPPA LLTQLLDKAS DPHLGTLSPE 

       310        320        330        340        350        360 
DSELETHDMF PDTIHSRSHH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG 

       370        380        390        400        410        420 
KEELSGSLLQ SVQEALEERS LTIRPALELQ ELDSPDDAIG TIKRAPFLGL PHTESTSGDN 

       430        440        450        460        470        480 
AQSCSPGTLS APPAGPGSPA LLPTAWATLK QQEDRERSSC HGLPPTPKVH MGACFSKVFN 

       490        500        510        520        530        540 
GCPLQIHAAV TWVHPVTRDQ FLVVGAEEGI YTLNLHELHE DTMEKLISQR CSWLYCVNNV 

       550        560        570        580        590        600 
LLSLSGKSTH IWAHDLPGLF EQRRLQHQAP LSIPTNRITQ RIIPRRFALS TKIPDTKGCL 

       610        620        630        640        650        660 
QCRVVRNPYT GSTFLLAALP ASLLLLQWYE PLQKFLLLKN FSSPLPSPAG MLEPLVLDGK 

       670        680        690        700        710        720 
ELPQVCVGAE GPEGPGCRVL FHVLPLEAGL TPDILIPPEG IPGSAQQVIQ VDRDTVLVSF 

       730        740        750        760        770        780 
ERCVRIVNLQ GEPTAALAPE LTFDFTIETV VCLQDSVLAF WSHGMQGRSL DTNEVTQEIT 

       790        800        810        820 
DETRIFRVLG AHRDIILESI PTDNPGAHSN LYILTGHQSS Y 

« Hide

References

« Hide 'large scale' references
[1]"In its active form, the GTP-binding protein rab8 interacts with a stress-activated protein kinase."
Ren M., Zeng J., De Lemos-Chiarandini C., Rosenfeld M., Adesnik M., Sabatini D.D.
Proc. Natl. Acad. Sci. U.S.A. 93:5151-5155(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH RAB8, SUBCELLULAR LOCATION.
Strain: BALB/c.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-821.
Strain: C57BL/6J.
Tissue: Embryo.
[3]"GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38."
Zhong J., Gavrilescu L.C., Molnar A., Murray L., Garafalo S., Kehrl J.H., Simon A.R., Van Etten R.A., Kyriakis J.M.
Proc. Natl. Acad. Sci. U.S.A. 106:4372-4377(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[4]"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.
[5]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U50595 mRNA. Translation: AAC52571.1.
AK051036 mRNA. Translation: BAC34507.1.
RefSeqNP_033032.1. NM_009006.2.
UniGeneMm.25860.

3D structure databases

ProteinModelPortalQ61161.
SMRQ61161. Positions 10-362.
ModBaseSearch...
MobiDBSearch...

PTM databases

PhosphoSiteQ61161.

Proteomic databases

PaxDbQ61161.
PRIDEQ61161.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000025897; ENSMUSP00000025897; ENSMUSG00000024948.
GeneID26412.
KEGGmmu:26412.
UCSCuc008gie.1. mouse.

Organism-specific databases

CTD5871.
MGIMGI:1346883. Map4k2.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00690000101936.
HOGENOMHOG000230824.
HOVERGENHBG036702.
InParanoidQ61161.
KOK04414.
OMAEIYHATG.
OrthoDBEOG7WX07M.
PhylomeDBQ61161.
TreeFamTF105121.

Gene expression databases

ArrayExpressQ61161.
BgeeQ61161.
GenevestigatorQ61161.

Family and domain databases

InterProIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
[Graphical view]
PfamPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF038172. MAPKKKK. 1 hit.
SMARTSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304405.
PROQ61161.
SOURCESearch...

Entry information

Entry nameM4K2_MOUSE
AccessionPrimary (citable) accession number: Q61161
Entry history
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot