Full text data of MAP4K2
MAP4K2
(GCK, RAB8IP)
[Confidence: low (only semi-automatic identification from reviews)]
Mitogen-activated protein kinase kinase kinase kinase 2; 2.7.11.1 (B lymphocyte serine/threonine-protein kinase; Germinal center kinase; GC kinase; MAPK/ERK kinase kinase kinase 2; MEK kinase kinase 2; MEKKK 2; Rab8-interacting protein)
Mitogen-activated protein kinase kinase kinase kinase 2; 2.7.11.1 (B lymphocyte serine/threonine-protein kinase; Germinal center kinase; GC kinase; MAPK/ERK kinase kinase kinase 2; MEK kinase kinase 2; MEKKK 2; Rab8-interacting protein)
UniProt
Q12851
ID M4K2_HUMAN Reviewed; 820 AA.
AC Q12851;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=B lymphocyte serine/threonine-protein kinase;
DE AltName: Full=Germinal center kinase;
DE Short=GC kinase;
DE AltName: Full=MAPK/ERK kinase kinase kinase 2;
DE Short=MEK kinase kinase 2;
DE Short=MEKKK 2;
DE AltName: Full=Rab8-interacting protein;
GN Name=MAP4K2; Synonyms=GCK, RAB8IP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-820, FUNCTION, DOMAIN, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Tonsil;
RX PubMed=7515885;
RA Katz P., Whalen G., Kehrl J.H.;
RT "Differential expression of a novel protein kinase in human B
RT lymphocytes. Preferential localization in the germinal center.";
RL J. Biol. Chem. 269:16802-16809(1994).
RN [3]
RP FUNCTION, AND ENZYME REGULATION.
RX PubMed=7477268; DOI=10.1038/377750a0;
RA Pombo C.M., Kehrl J.H., Sanchez I., Katz P., Avruch J., Zon L.I.,
RA Woodgett J.R., Force T., Kyriakis J.M.;
RT "Activation of the SAPK pathway by the human STE20 homologue germinal
RT centre kinase.";
RL Nature 377:750-754(1995).
RN [4]
RP FUNCTION, AUTOPHOSPHORYLATION, AND INTERACTION WITH MAP3K1/MEKK1 AND
RP TRAF2.
RX PubMed=9712898; DOI=10.1074/jbc.273.35.22681;
RA Yuasa T., Ohno S., Kehrl J.H., Kyriakis J.M.;
RT "Tumor necrosis factor signaling to stress-activated protein kinase
RT (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase
RT couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1
RT and SAPK while receptor interacting protein associates with a mitogen-
RT activated protein kinase kinase kinase upstream of MKK6 and p38.";
RL J. Biol. Chem. 273:22681-22692(1998).
RN [5]
RP FUNCTION, AND INTERACTION WITH TRAF2 AND MAP3K1.
RX PubMed=11784851; DOI=10.1128/MCB.22.3.737-749.2002;
RA Chadee D.N., Yuasa T., Kyriakis J.M.;
RT "Direct activation of mitogen-activated protein kinase kinase kinase
RT MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2.";
RL Mol. Cell. Biol. 22:737-749(2002).
RN [6]
RP ENZYME REGULATION, FUNCTION, UBIQUITINATION, AND INTERACTION WITH
RP TRAF6.
RX PubMed=15456887; DOI=10.1128/MCB.24.20.9165-9175.2004;
RA Zhong J., Kyriakis J.M.;
RT "Germinal center kinase is required for optimal Jun N-terminal kinase
RT activation by Toll-like receptor agonists and is regulated by the
RT ubiquitin proteasome system and agonist-induced, TRAF6-dependent
RT stabilization.";
RL Mol. Cell. Biol. 24:9165-9175(2004).
RN [7]
RP FUNCTION, AND INTERACTION WITH MAP3K11/MLK3.
RX PubMed=17584736; DOI=10.1074/jbc.M703422200;
RA Zhong J., Kyriakis J.M.;
RT "Dissection of a signaling pathway by which pathogen-associated
RT molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine
RT release.";
RL J. Biol. Chem. 282:24246-24254(2007).
RN [8]
RP REVIEW ON FUNCTION.
RX PubMed=10026130; DOI=10.1074/jbc.274.9.5259;
RA Kyriakis J.M.;
RT "Signaling by the germinal center kinase family of protein kinases.";
RL J. Biol. Chem. 274:5259-5262(1999).
RN [9]
RP REVIEW ON FUNCTION.
RX PubMed=11316611; DOI=10.1016/S0962-8924(01)01980-8;
RA Dan I., Watanabe N.M., Kusumi A.;
RT "The Ste20 group kinases as regulators of MAP kinase cascades.";
RL Trends Cell Biol. 11:220-230(2001).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
CC -!- FUNCTION: Serine/threonine-protein kinase which acts as an
CC essential component of the MAP kinase signal transduction pathway.
CC Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream
CC activator of the stress-activated protein kinase/c-Jun N-terminal
CC kinase (SAP/JNK) signaling pathway and to a lesser extend of the
CC p38 MAPKs signaling pathway. Required for the efficient activation
CC of JNKs by TRAF6-dependent stimuli, including pathogen-associated
CC molecular patterns (PAMPs) such as polyinosine-polycytidine
CC (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan
CC (PGN), or bacterial flagellin. To a lesser degree, IL-1 and
CC engagement of CD40 also stimulate MAP4K2-mediated JNKs activation.
CC The requirement for MAP4K2/GCK is most pronounced for LPS
CC signaling, and extends to LPS stimulation of c-Jun phosphorylation
CC and induction of IL-8. Enhances MAP3K1 oligomerization, which may
CC relieve N-terminal mediated MAP3K1 autoinhibition and lead to
CC activation following autophosphorylation. Mediates also the
CC SAP/JNK signaling pathway and the p38 MAPKs signaling pathway
CC through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3.
CC May play a role in the regulation of vesicle targeting or fusion.
CC regulation of vesicle targeting or fusion.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: The tumor necrosis factor (TNF), as well as
CC endotoxins and proinflammatory stimuli such as polyinosine-
CC polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan
CC (PGN), flagellin, or lipid A activate MAP4K2 by promoting its
CC autophosphorylation.
CC -!- SUBUNIT: Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and
CC MAP3K11/MLK3. Interacts with RAB8A (By similarity).
CC -!- INTERACTION:
CC Q13233:MAP3K1; NbExp=2; IntAct=EBI-49783, EBI-49776;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Basolateral cell
CC membrane; Peripheral membrane protein (By similarity). Golgi
CC apparatus membrane; Peripheral membrane protein (By similarity).
CC -!- TISSUE SPECIFICITY: Highly expressed in germinal center but not
CC mantle zone B-cells. Also expressed in lung, brain and placenta
CC and at lower levels in other tissues examined.
CC -!- DOMAIN: The PEST domains are Pro-, Glu-, Ser-, and Thr-rich
CC domains. Proteins with PEST domains are frequently targets of
CC degradation by the ubiquitin proteasome.
CC -!- PTM: Polyubiquitinated through 'Lys-48'-polyubiquitin chains,
CC allowing proteasomal turnover. Ubiquitination requires the kinase
CC activity of MAP4K2/GCK.
CC -!- PTM: Autophosphorylated in response to tumor necrosis factor
CC (TNF), endotoxins or proinflammatory stimuli. Autophosphorylation
CC leads to activation.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily.
CC -!- SIMILARITY: Contains 1 CNH domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA20968.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part;
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DR EMBL; AP001462; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U07349; AAA20968.1; ALT_SEQ; mRNA.
DR PIR; A53714; A53714.
DR RefSeq; NP_004570.2; NM_004579.3.
DR UniGene; Hs.534341; -.
DR ProteinModelPortal; Q12851; -.
DR SMR; Q12851; 11-389.
DR IntAct; Q12851; 11.
DR MINT; MINT-8247528; -.
DR STRING; 9606.ENSP00000294066; -.
DR BindingDB; Q12851; -.
DR ChEMBL; CHEMBL5330; -.
DR GuidetoPHARMACOLOGY; 2086; -.
DR PhosphoSite; Q12851; -.
DR DMDM; 215274019; -.
DR PaxDb; Q12851; -.
DR PRIDE; Q12851; -.
DR DNASU; 5871; -.
DR Ensembl; ENST00000294066; ENSP00000294066; ENSG00000168067.
DR GeneID; 5871; -.
DR KEGG; hsa:5871; -.
DR UCSC; uc001obh.3; human.
DR CTD; 5871; -.
DR GeneCards; GC11M064556; -.
DR H-InvDB; HIX0026186; -.
DR HGNC; HGNC:6864; MAP4K2.
DR HPA; HPA007330; -.
DR MIM; 603166; gene.
DR neXtProt; NX_Q12851; -.
DR PharmGKB; PA30610; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000230824; -.
DR HOVERGEN; HBG036702; -.
DR InParanoid; Q12851; -.
DR KO; K04414; -.
DR OMA; EIYHATG; -.
DR PhylomeDB; Q12851; -.
DR SignaLink; Q12851; -.
DR GeneWiki; MAP4K2; -.
DR GenomeRNAi; 5871; -.
DR NextBio; 22804; -.
DR PRO; PR:Q12851; -.
DR ArrayExpress; Q12851; -.
DR Bgee; Q12851; -.
DR CleanEx; HS_GCK; -.
DR CleanEx; HS_MAP4K2; -.
DR Genevestigator; Q12851; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0005083; F:small GTPase regulator activity; IEA:InterPro.
DR GO; GO:0007257; P:activation of JUN kinase activity; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0006903; P:vesicle targeting; NAS:UniProtKB.
DR InterPro; IPR001180; Citron.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR021160; MAPKKKK.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038172; MAPKKKK; 1.
DR SMART; SM00036; CNH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50219; CNH; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Complete proteome; Cytoplasm;
KW Golgi apparatus; Immunity; Innate immunity; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Ubl conjugation.
FT CHAIN 1 820 Mitogen-activated protein kinase kinase
FT kinase kinase 2.
FT /FTId=PRO_0000086275.
FT DOMAIN 16 273 Protein kinase.
FT DOMAIN 482 793 CNH.
FT NP_BIND 22 30 ATP (By similarity).
FT REGION 294 314 PEST1.
FT REGION 344 360 PEST2.
FT REGION 405 448 PEST3.
FT ACT_SITE 136 136 Proton acceptor (By similarity).
FT BINDING 45 45 ATP (By similarity).
FT MOD_RES 394 394 Phosphoserine.
FT CONFLICT 120 120 A -> R (in Ref. 2; AAA20968).
SQ SEQUENCE 820 AA; 91556 MW; A59C1E99BFFAEF41 CRC64;
MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD PGDDISSLQQ
EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE IYHATGPLEE RQIAYVCREA
LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV KLADFGVSGE LTASVAKRRS FIGTPYWMAP
EVAAVERKGG YNELCDVWAL GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT
RWTQNFHHFL KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE
DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG
KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG TIKRAPFLGP LPTDPPAEEP
LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ REDPERSSCH GLPPTPKVHM GACFSKVFNG
CPLRIHAAVT WIHPVTRDQF LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL
LSLSGKSTHI WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ
CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM LEPLVLDGKE
LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI PGSAQQVIQV DRDTILVSFE
RCVRIVNMQG EPTATLAPEL TFDFPIETVV CLQDSVLAFW SHGMQGRSLD TNEVTQEITD
ETRIFRVLGA HRDIILESIP TDNPEAHSNL YILTGHQSTY
//
ID M4K2_HUMAN Reviewed; 820 AA.
AC Q12851;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=B lymphocyte serine/threonine-protein kinase;
DE AltName: Full=Germinal center kinase;
DE Short=GC kinase;
DE AltName: Full=MAPK/ERK kinase kinase kinase 2;
DE Short=MEK kinase kinase 2;
DE Short=MEKKK 2;
DE AltName: Full=Rab8-interacting protein;
GN Name=MAP4K2; Synonyms=GCK, RAB8IP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-820, FUNCTION, DOMAIN, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Tonsil;
RX PubMed=7515885;
RA Katz P., Whalen G., Kehrl J.H.;
RT "Differential expression of a novel protein kinase in human B
RT lymphocytes. Preferential localization in the germinal center.";
RL J. Biol. Chem. 269:16802-16809(1994).
RN [3]
RP FUNCTION, AND ENZYME REGULATION.
RX PubMed=7477268; DOI=10.1038/377750a0;
RA Pombo C.M., Kehrl J.H., Sanchez I., Katz P., Avruch J., Zon L.I.,
RA Woodgett J.R., Force T., Kyriakis J.M.;
RT "Activation of the SAPK pathway by the human STE20 homologue germinal
RT centre kinase.";
RL Nature 377:750-754(1995).
RN [4]
RP FUNCTION, AUTOPHOSPHORYLATION, AND INTERACTION WITH MAP3K1/MEKK1 AND
RP TRAF2.
RX PubMed=9712898; DOI=10.1074/jbc.273.35.22681;
RA Yuasa T., Ohno S., Kehrl J.H., Kyriakis J.M.;
RT "Tumor necrosis factor signaling to stress-activated protein kinase
RT (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase
RT couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1
RT and SAPK while receptor interacting protein associates with a mitogen-
RT activated protein kinase kinase kinase upstream of MKK6 and p38.";
RL J. Biol. Chem. 273:22681-22692(1998).
RN [5]
RP FUNCTION, AND INTERACTION WITH TRAF2 AND MAP3K1.
RX PubMed=11784851; DOI=10.1128/MCB.22.3.737-749.2002;
RA Chadee D.N., Yuasa T., Kyriakis J.M.;
RT "Direct activation of mitogen-activated protein kinase kinase kinase
RT MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2.";
RL Mol. Cell. Biol. 22:737-749(2002).
RN [6]
RP ENZYME REGULATION, FUNCTION, UBIQUITINATION, AND INTERACTION WITH
RP TRAF6.
RX PubMed=15456887; DOI=10.1128/MCB.24.20.9165-9175.2004;
RA Zhong J., Kyriakis J.M.;
RT "Germinal center kinase is required for optimal Jun N-terminal kinase
RT activation by Toll-like receptor agonists and is regulated by the
RT ubiquitin proteasome system and agonist-induced, TRAF6-dependent
RT stabilization.";
RL Mol. Cell. Biol. 24:9165-9175(2004).
RN [7]
RP FUNCTION, AND INTERACTION WITH MAP3K11/MLK3.
RX PubMed=17584736; DOI=10.1074/jbc.M703422200;
RA Zhong J., Kyriakis J.M.;
RT "Dissection of a signaling pathway by which pathogen-associated
RT molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine
RT release.";
RL J. Biol. Chem. 282:24246-24254(2007).
RN [8]
RP REVIEW ON FUNCTION.
RX PubMed=10026130; DOI=10.1074/jbc.274.9.5259;
RA Kyriakis J.M.;
RT "Signaling by the germinal center kinase family of protein kinases.";
RL J. Biol. Chem. 274:5259-5262(1999).
RN [9]
RP REVIEW ON FUNCTION.
RX PubMed=11316611; DOI=10.1016/S0962-8924(01)01980-8;
RA Dan I., Watanabe N.M., Kusumi A.;
RT "The Ste20 group kinases as regulators of MAP kinase cascades.";
RL Trends Cell Biol. 11:220-230(2001).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
CC -!- FUNCTION: Serine/threonine-protein kinase which acts as an
CC essential component of the MAP kinase signal transduction pathway.
CC Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream
CC activator of the stress-activated protein kinase/c-Jun N-terminal
CC kinase (SAP/JNK) signaling pathway and to a lesser extend of the
CC p38 MAPKs signaling pathway. Required for the efficient activation
CC of JNKs by TRAF6-dependent stimuli, including pathogen-associated
CC molecular patterns (PAMPs) such as polyinosine-polycytidine
CC (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan
CC (PGN), or bacterial flagellin. To a lesser degree, IL-1 and
CC engagement of CD40 also stimulate MAP4K2-mediated JNKs activation.
CC The requirement for MAP4K2/GCK is most pronounced for LPS
CC signaling, and extends to LPS stimulation of c-Jun phosphorylation
CC and induction of IL-8. Enhances MAP3K1 oligomerization, which may
CC relieve N-terminal mediated MAP3K1 autoinhibition and lead to
CC activation following autophosphorylation. Mediates also the
CC SAP/JNK signaling pathway and the p38 MAPKs signaling pathway
CC through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3.
CC May play a role in the regulation of vesicle targeting or fusion.
CC regulation of vesicle targeting or fusion.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: The tumor necrosis factor (TNF), as well as
CC endotoxins and proinflammatory stimuli such as polyinosine-
CC polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan
CC (PGN), flagellin, or lipid A activate MAP4K2 by promoting its
CC autophosphorylation.
CC -!- SUBUNIT: Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and
CC MAP3K11/MLK3. Interacts with RAB8A (By similarity).
CC -!- INTERACTION:
CC Q13233:MAP3K1; NbExp=2; IntAct=EBI-49783, EBI-49776;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Basolateral cell
CC membrane; Peripheral membrane protein (By similarity). Golgi
CC apparatus membrane; Peripheral membrane protein (By similarity).
CC -!- TISSUE SPECIFICITY: Highly expressed in germinal center but not
CC mantle zone B-cells. Also expressed in lung, brain and placenta
CC and at lower levels in other tissues examined.
CC -!- DOMAIN: The PEST domains are Pro-, Glu-, Ser-, and Thr-rich
CC domains. Proteins with PEST domains are frequently targets of
CC degradation by the ubiquitin proteasome.
CC -!- PTM: Polyubiquitinated through 'Lys-48'-polyubiquitin chains,
CC allowing proteasomal turnover. Ubiquitination requires the kinase
CC activity of MAP4K2/GCK.
CC -!- PTM: Autophosphorylated in response to tumor necrosis factor
CC (TNF), endotoxins or proinflammatory stimuli. Autophosphorylation
CC leads to activation.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily.
CC -!- SIMILARITY: Contains 1 CNH domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA20968.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part;
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DR EMBL; AP001462; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U07349; AAA20968.1; ALT_SEQ; mRNA.
DR PIR; A53714; A53714.
DR RefSeq; NP_004570.2; NM_004579.3.
DR UniGene; Hs.534341; -.
DR ProteinModelPortal; Q12851; -.
DR SMR; Q12851; 11-389.
DR IntAct; Q12851; 11.
DR MINT; MINT-8247528; -.
DR STRING; 9606.ENSP00000294066; -.
DR BindingDB; Q12851; -.
DR ChEMBL; CHEMBL5330; -.
DR GuidetoPHARMACOLOGY; 2086; -.
DR PhosphoSite; Q12851; -.
DR DMDM; 215274019; -.
DR PaxDb; Q12851; -.
DR PRIDE; Q12851; -.
DR DNASU; 5871; -.
DR Ensembl; ENST00000294066; ENSP00000294066; ENSG00000168067.
DR GeneID; 5871; -.
DR KEGG; hsa:5871; -.
DR UCSC; uc001obh.3; human.
DR CTD; 5871; -.
DR GeneCards; GC11M064556; -.
DR H-InvDB; HIX0026186; -.
DR HGNC; HGNC:6864; MAP4K2.
DR HPA; HPA007330; -.
DR MIM; 603166; gene.
DR neXtProt; NX_Q12851; -.
DR PharmGKB; PA30610; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000230824; -.
DR HOVERGEN; HBG036702; -.
DR InParanoid; Q12851; -.
DR KO; K04414; -.
DR OMA; EIYHATG; -.
DR PhylomeDB; Q12851; -.
DR SignaLink; Q12851; -.
DR GeneWiki; MAP4K2; -.
DR GenomeRNAi; 5871; -.
DR NextBio; 22804; -.
DR PRO; PR:Q12851; -.
DR ArrayExpress; Q12851; -.
DR Bgee; Q12851; -.
DR CleanEx; HS_GCK; -.
DR CleanEx; HS_MAP4K2; -.
DR Genevestigator; Q12851; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; TAS:ProtInc.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0005083; F:small GTPase regulator activity; IEA:InterPro.
DR GO; GO:0007257; P:activation of JUN kinase activity; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0006903; P:vesicle targeting; NAS:UniProtKB.
DR InterPro; IPR001180; Citron.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR021160; MAPKKKK.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR Pfam; PF00780; CNH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF038172; MAPKKKK; 1.
DR SMART; SM00036; CNH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50219; CNH; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Complete proteome; Cytoplasm;
KW Golgi apparatus; Immunity; Innate immunity; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Ubl conjugation.
FT CHAIN 1 820 Mitogen-activated protein kinase kinase
FT kinase kinase 2.
FT /FTId=PRO_0000086275.
FT DOMAIN 16 273 Protein kinase.
FT DOMAIN 482 793 CNH.
FT NP_BIND 22 30 ATP (By similarity).
FT REGION 294 314 PEST1.
FT REGION 344 360 PEST2.
FT REGION 405 448 PEST3.
FT ACT_SITE 136 136 Proton acceptor (By similarity).
FT BINDING 45 45 ATP (By similarity).
FT MOD_RES 394 394 Phosphoserine.
FT CONFLICT 120 120 A -> R (in Ref. 2; AAA20968).
SQ SEQUENCE 820 AA; 91556 MW; A59C1E99BFFAEF41 CRC64;
MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD PGDDISSLQQ
EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE IYHATGPLEE RQIAYVCREA
LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV KLADFGVSGE LTASVAKRRS FIGTPYWMAP
EVAAVERKGG YNELCDVWAL GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT
RWTQNFHHFL KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE
DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG
KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG TIKRAPFLGP LPTDPPAEEP
LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ REDPERSSCH GLPPTPKVHM GACFSKVFNG
CPLRIHAAVT WIHPVTRDQF LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL
LSLSGKSTHI WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ
CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM LEPLVLDGKE
LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI PGSAQQVIQV DRDTILVSFE
RCVRIVNMQG EPTATLAPEL TFDFPIETVV CLQDSVLAFW SHGMQGRSLD TNEVTQEITD
ETRIFRVLGA HRDIILESIP TDNPEAHSNL YILTGHQSTY
//
MIM
603166
*RECORD*
*FIELD* NO
603166
*FIELD* TI
*603166 MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 2; MAP4K2
;;GERMINAL CENTER KINASE; GCK;;
read moreRAB8-INTERACTING PROTEIN, FORMERLY; RAB8IP, FORMERLY
*FIELD* TX
CLONING
B lymphocytes that reside in the germinal center of lymphoid follicles
are functionally and phenotypically distinct from those residing in the
surrounding mantle zone. Various regulatory and structural genes control
a complex series of differentiation and selection steps through which B
cells that exit the germinal center of lymphoid follicles must pass. In
differential hybridization studies to identify some of these genes, Katz
et al. (1994) isolated a novel gene based on its preferential expression
in tonsillar germinal center B lymphocytes. The complete nucleotide
sequence predicted an 819-amino acid protein, named GC (for 'germinal
center') kinase, with homology to serine-threonine protein kinases. Its
catalytic domain was 39% and 37% identical to those of S. cerevisiae
STE20 and Drosophila ninaC proteins, respectively. Northern blot
analysis revealed expression of a 2.9-kb mRNA in several human tissues,
including brain, lung, and placenta. In situ hybridization of tonsil
tissue demonstrated preferential hybridization to the germinal center
region. The expressed protein phosphorylated casein and myelin basic
protein in in vitro kinase assays.
GENE FUNCTION
Pombo et al. (1995) showed that GC kinase specifically activates the
SAPK (601335) pathway. They also showed that GCK is activated in situ by
TNF-alpha (191160), a potent SAPK agonist. The authors suggested that
the SAPK pathway may be active in the differentiation and selection of B
cells in the germinal center.
Ren et al. (1996) identified a mouse protein based on its interaction
with the vesicular transport protein Rab8 (165040). This mouse protein,
termed Rab8ip, and GC kinase shared 93% amino acid sequence identity.
Rab8ip/GC kinase had serine/threonine protein kinase activity manifested
both as autophosphorylation and phosphorylation of casein and myelin
basic protein. Based on its interaction with Rab8, the authors suggested
that Rab8ip/GC kinase may modulate secretion in response to stress
stimuli.
MAPPING
Guru et al. (1997) mapped and sequenced the MEN I (MEN1; 131100) genomic
region at 11q13. They identified MAP4K2 in this region between PYGM
(608455) and marker D11S4936.
*FIELD* RF
1. Guru, S. C.; Agarwal, S. K.; Manickam, P.; Olufemi, S.-E.; Crabtree,
J. S.; Weisemann, J. M.; Kester, M. B.; Kim, Y. S.; Wang, Y.; Emmert-Buck,
M. R.; Liotta, L. A.; Spiegel, A. M.; Boguski, M. S.; Roe, B. A.;
Collins, F. S.; Marx, S. J.; Burns, L.; Chandrasekharappa, S. C.:
A transcript map for the 2.8-Mb region containing the multiple endocrine
neoplasia type 1 locus. Genome Res. 7: 725-735, 1997.
2. Katz, P.; Whalen, G.; Kehrl, J. H.: Differential expression of
a novel protein kinase in human B lymphocytes: preferential localization
in the germinal center. J. Biol. Chem. 269: 16802-16809, 1994.
3. Pombo, C. M.; Kehrl, J. H.; Sanchez, I.; Katz, P.; Avruch, J.;
Zon, L. I.; Woodgett, J. R.; Force, T.; Kyriakis, J. M.: Activation
of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 377:
750-754, 1995.
4. Ren, M.; Zeng, J.; De Lemos-Chiarandini, C.; Rosenfeld, M.; Adesnik,
M.; Sabatini, D. D.: In its active form, the GTP-binding protein
rab8 interacts with a stress-activated protein kinase. Proc. Nat.
Acad. Sci. 93: 5151-5155, 1996.
*FIELD* CD
Jennifer P. Macke: 10/20/1998
*FIELD* ED
carol: 02/09/2011
alopez: 5/7/2010
carol: 6/2/2005
carol: 3/9/2004
carol: 8/13/2003
mgross: 5/5/2000
mgross: 9/16/1999
alopez: 3/22/1999
alopez: 10/20/1998
*RECORD*
*FIELD* NO
603166
*FIELD* TI
*603166 MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 2; MAP4K2
;;GERMINAL CENTER KINASE; GCK;;
read moreRAB8-INTERACTING PROTEIN, FORMERLY; RAB8IP, FORMERLY
*FIELD* TX
CLONING
B lymphocytes that reside in the germinal center of lymphoid follicles
are functionally and phenotypically distinct from those residing in the
surrounding mantle zone. Various regulatory and structural genes control
a complex series of differentiation and selection steps through which B
cells that exit the germinal center of lymphoid follicles must pass. In
differential hybridization studies to identify some of these genes, Katz
et al. (1994) isolated a novel gene based on its preferential expression
in tonsillar germinal center B lymphocytes. The complete nucleotide
sequence predicted an 819-amino acid protein, named GC (for 'germinal
center') kinase, with homology to serine-threonine protein kinases. Its
catalytic domain was 39% and 37% identical to those of S. cerevisiae
STE20 and Drosophila ninaC proteins, respectively. Northern blot
analysis revealed expression of a 2.9-kb mRNA in several human tissues,
including brain, lung, and placenta. In situ hybridization of tonsil
tissue demonstrated preferential hybridization to the germinal center
region. The expressed protein phosphorylated casein and myelin basic
protein in in vitro kinase assays.
GENE FUNCTION
Pombo et al. (1995) showed that GC kinase specifically activates the
SAPK (601335) pathway. They also showed that GCK is activated in situ by
TNF-alpha (191160), a potent SAPK agonist. The authors suggested that
the SAPK pathway may be active in the differentiation and selection of B
cells in the germinal center.
Ren et al. (1996) identified a mouse protein based on its interaction
with the vesicular transport protein Rab8 (165040). This mouse protein,
termed Rab8ip, and GC kinase shared 93% amino acid sequence identity.
Rab8ip/GC kinase had serine/threonine protein kinase activity manifested
both as autophosphorylation and phosphorylation of casein and myelin
basic protein. Based on its interaction with Rab8, the authors suggested
that Rab8ip/GC kinase may modulate secretion in response to stress
stimuli.
MAPPING
Guru et al. (1997) mapped and sequenced the MEN I (MEN1; 131100) genomic
region at 11q13. They identified MAP4K2 in this region between PYGM
(608455) and marker D11S4936.
*FIELD* RF
1. Guru, S. C.; Agarwal, S. K.; Manickam, P.; Olufemi, S.-E.; Crabtree,
J. S.; Weisemann, J. M.; Kester, M. B.; Kim, Y. S.; Wang, Y.; Emmert-Buck,
M. R.; Liotta, L. A.; Spiegel, A. M.; Boguski, M. S.; Roe, B. A.;
Collins, F. S.; Marx, S. J.; Burns, L.; Chandrasekharappa, S. C.:
A transcript map for the 2.8-Mb region containing the multiple endocrine
neoplasia type 1 locus. Genome Res. 7: 725-735, 1997.
2. Katz, P.; Whalen, G.; Kehrl, J. H.: Differential expression of
a novel protein kinase in human B lymphocytes: preferential localization
in the germinal center. J. Biol. Chem. 269: 16802-16809, 1994.
3. Pombo, C. M.; Kehrl, J. H.; Sanchez, I.; Katz, P.; Avruch, J.;
Zon, L. I.; Woodgett, J. R.; Force, T.; Kyriakis, J. M.: Activation
of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 377:
750-754, 1995.
4. Ren, M.; Zeng, J.; De Lemos-Chiarandini, C.; Rosenfeld, M.; Adesnik,
M.; Sabatini, D. D.: In its active form, the GTP-binding protein
rab8 interacts with a stress-activated protein kinase. Proc. Nat.
Acad. Sci. 93: 5151-5155, 1996.
*FIELD* CD
Jennifer P. Macke: 10/20/1998
*FIELD* ED
carol: 02/09/2011
alopez: 5/7/2010
carol: 6/2/2005
carol: 3/9/2004
carol: 8/13/2003
mgross: 5/5/2000
mgross: 9/16/1999
alopez: 3/22/1999
alopez: 10/20/1998