Q61161 (M4K2_MOUSE) 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):
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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	821 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.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 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 electronic annotation. Source: Compara innate immune response Inferred from electronic annotation. Source: UniProtKB-KW intracellular protein kinase cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara protein phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB vesicle targeting Inferred from direct assay Ref.1. Source: UniProtKB
Cellular_component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell basolateral plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW small GTPase regulator activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 821	821	Mitogen-activated protein kinase kinase kinase kinase 2		PRO_0000086276
Regions
	Domain	16 – 273	258	Protein kinase
	Domain	483 – 794	312	CNH
	Nucleotide binding	22 – 30	9	ATP By similarity UniProtKB O00506
	Region	294 – 314	21	PEST1
	Region	344 – 360	17	PEST2
	Region	405 – 449	45	PEST3
Sites
	Active site	136	1	Proton acceptor By similarity UniProtKB O00506
	Binding site	45	1	ATP By similarity UniProtKB O00506
Amino acid modifications
	Modified residue	394	1	Phosphoserine By similarity
Experimental info
	Sequence conflict	223	1	L → M in BAC34507. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q61161 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 2CCF750E45A53B05	FASTA	821	91,265
	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

References

	« Hide 'large scale' referencesShow '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. , 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.
IPI	IPI00117889.
RefSeq	NP_033032.1. NM_009006.2.
UniGene	Mm.25860.
3D structure databases
ProteinModelPortal	Q61161.
SMR	Q61161. Positions 11-362.
ModBase	Search...
PTM databases
PhosphoSite	Q61161.
Proteomic databases
PaxDb	Q61161.
PRIDE	Q61161.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000025897; ENSMUSP00000025897; ENSMUSG00000024948.
GeneID	26412.
KEGG	mmu:26412.
UCSC	uc008gie.1. mouse.
Organism-specific databases
CTD	5871.
MGI	MGI:1346883. Map4k2.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00690000101936.
HOGENOM	HOG000230824.
HOVERGEN	HBG036702.
InParanoid	Q61161.
KO	K04414.
OMA	PGLFEQR.
OrthoDB	EOG4V6ZG4.
Gene expression databases
ArrayExpress	Q61161.
Bgee	Q61161.
Genevestigator	Q61161.
GermOnline	ENSMUSG00000024948. Mus musculus.
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
NextBio	304405.
SOURCE	Search...

Entry information

Entry name

M4K2_MOUSE

Accession

Primary (citable) accession number: Q61161

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 28, 2003
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program