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Protein

Mitogen-activated protein kinase kinase kinase kinase 2

Gene

Map4k2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.2 Publications

Catalytic activityi

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

Cofactori

Mg2+1 Publication

Enzyme regulationi

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei45 – 451ATPPROSITE-ProRule annotation
Active sitei136 – 1361Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi22 – 309ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB
  2. mitogen-activated protein kinase kinase kinase binding Source: MGI
  3. protein serine/threonine kinase activity Source: MGI
  4. receptor signaling protein serine/threonine kinase activity Source: GO_Central

GO - Biological processi

  1. activation of JUN kinase activity Source: MGI
  2. innate immune response Source: UniProtKB-KW
  3. intracellular signal transduction Source: UniProtKB
  4. positive regulation of JNK cascade Source: MGI
  5. protein phosphorylation Source: UniProtKB
  6. vesicle targeting Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Immunity, Innate immunity, Stress response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Map4k2
Synonyms:Rab8ip
OrganismiMus musculus (Mouse)Imported
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 19

Organism-specific databases

MGIiMGI:1346883. Map4k2.

Subcellular locationi

  1. Cytoplasm 1 Publication
  2. Basolateral cell membrane 1 Publication; Peripheral membrane protein 1 Publication
  3. Golgi apparatus membrane 1 Publication; Peripheral membrane protein 1 Publication

GO - Cellular componenti

  1. basolateral plasma membrane Source: UniProtKB-SubCell
  2. cytoplasm Source: GO_Central
  3. Golgi membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Golgi apparatus, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 821821Mitogen-activated protein kinase kinase kinase kinase 2PRO_0000086276Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei394 – 3941PhosphoserineBy similarity

Post-translational modificationi

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.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ61161.
PaxDbiQ61161.
PRIDEiQ61161.

PTM databases

PhosphoSiteiQ61161.

Expressioni

Gene expression databases

BgeeiQ61161.
ExpressionAtlasiQ61161. baseline and differential.
GenevestigatoriQ61161.

Interactioni

Subunit structurei

Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3 (By similarity). Interacts with RAB8A.By similarity1 Publication

Structurei

3D structure databases

ProteinModelPortaliQ61161.
SMRiQ61161. Positions 10-362.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini16 – 273258Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini483 – 794312CNHPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni294 – 31421PEST1Add
BLAST
Regioni344 – 36017PEST2Add
BLAST
Regioni405 – 44945PEST3Add
BLAST

Domaini

The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome.

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118848.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ61161.
KOiK04414.
OMAiAWATMKQ.
OrthoDBiEOG7WX07M.
PhylomeDBiQ61161.
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. 1 hit.
PROSITEiPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q61161-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD
60 70 80 90 100
PGDDISSLQQ EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE
110 120 130 140 150
IYHATGPLEE RQIAYVCREA LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV
160 170 180 190 200
KLADFGVSGE LTASVAKRRS FIGTPYWMAP EVAAVERKGG YNELCDVWAL
210 220 230 240 250
GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT RWTQNFHHFL
260 270 280 290 300
KLALTKNPKK RPTAERLLQH PFTTQHLPPA LLTQLLDKAS DPHLGTLSPE
310 320 330 340 350
DSELETHDMF PDTIHSRSHH GPAERTPSEI QFHQVKFGAP RRKETDPLNE
360 370 380 390 400
PWEEEWTLLG KEELSGSLLQ SVQEALEERS LTIRPALELQ ELDSPDDAIG
410 420 430 440 450
TIKRAPFLGL PHTESTSGDN AQSCSPGTLS APPAGPGSPA LLPTAWATLK
460 470 480 490 500
QQEDRERSSC HGLPPTPKVH MGACFSKVFN GCPLQIHAAV TWVHPVTRDQ
510 520 530 540 550
FLVVGAEEGI YTLNLHELHE DTMEKLISQR CSWLYCVNNV LLSLSGKSTH
560 570 580 590 600
IWAHDLPGLF EQRRLQHQAP LSIPTNRITQ RIIPRRFALS TKIPDTKGCL
610 620 630 640 650
QCRVVRNPYT GSTFLLAALP ASLLLLQWYE PLQKFLLLKN FSSPLPSPAG
660 670 680 690 700
MLEPLVLDGK ELPQVCVGAE GPEGPGCRVL FHVLPLEAGL TPDILIPPEG
710 720 730 740 750
IPGSAQQVIQ VDRDTVLVSF ERCVRIVNLQ GEPTAALAPE LTFDFTIETV
760 770 780 790 800
VCLQDSVLAF WSHGMQGRSL DTNEVTQEIT DETRIFRVLG AHRDIILESI
810 820
PTDNPGAHSN LYILTGHQSS Y
Length:821
Mass (Da):91,265
Last modified:November 1, 1996 - v1
Checksum:i2CCF750E45A53B05
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti223 – 2231L → M in BAC34507 (PubMed:16141072).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U50595 mRNA. Translation: AAC52571.1.
AK051036 mRNA. Translation: BAC34507.1.
CCDSiCCDS29503.1.
RefSeqiNP_001278716.1. NM_001291787.1.
NP_033032.1. NM_009006.3.
UniGeneiMm.25860.

Genome annotation databases

EnsembliENSMUST00000025897; ENSMUSP00000025897; ENSMUSG00000024948.
GeneIDi26412.
KEGGimmu:26412.
UCSCiuc008gie.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U50595 mRNA. Translation: AAC52571.1.
AK051036 mRNA. Translation: BAC34507.1.
CCDSiCCDS29503.1.
RefSeqiNP_001278716.1. NM_001291787.1.
NP_033032.1. NM_009006.3.
UniGeneiMm.25860.

3D structure databases

ProteinModelPortaliQ61161.
SMRiQ61161. Positions 10-362.
ModBaseiSearch...
MobiDBiSearch...

PTM databases

PhosphoSiteiQ61161.

Proteomic databases

MaxQBiQ61161.
PaxDbiQ61161.
PRIDEiQ61161.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000025897; ENSMUSP00000025897; ENSMUSG00000024948.
GeneIDi26412.
KEGGimmu:26412.
UCSCiuc008gie.1. mouse.

Organism-specific databases

CTDi5871.
MGIiMGI:1346883. Map4k2.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118848.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ61161.
KOiK04414.
OMAiAWATMKQ.
OrthoDBiEOG7WX07M.
PhylomeDBiQ61161.
TreeFamiTF105121.

Miscellaneous databases

NextBioi304405.
PROiQ61161.
SOURCEiSearch...

Gene expression databases

BgeeiQ61161.
ExpressionAtlasiQ61161. baseline and differential.
GenevestigatoriQ61161.

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. 1 hit.
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. "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.
    , 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.

Entry informationi

Entry nameiM4K2_MOUSE
AccessioniPrimary (citable) accession number: Q61161
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 1, 1996
Last modified: April 29, 2015
This is version 126 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. 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.