ID   M4K2_MOUSE              Reviewed;         821 AA.
AC   Q61161;
DT   28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   24-JAN-2024, entry version 179.
DE   RecName: Full=Mitogen-activated protein kinase kinase kinase kinase 2;
DE            EC=2.7.11.1;
DE   AltName: Full=Germinal center kinase;
DE            Short=GCK;
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=Rab8ip;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090 {ECO:0000312|EMBL:AAC52571.1};
RN   [1] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH RAB8, AND
RP   SUBCELLULAR LOCATION.
RC   STRAIN=BALB/cJ;
RX   PubMed=8643544; DOI=10.1073/pnas.93.10.5151;
RA   Ren M., Zeng J., De Lemos-Chiarandini C., Rosenfeld M., Adesnik M.,
RA   Sabatini D.D.;
RT   "In its active form, the GTP-binding protein rab8 interacts with a stress-
RT   activated protein kinase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:5151-5155(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-821.
RC   STRAIN=C57BL/6J; TISSUE=Embryo;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   RETRACTED PAPER.
RX   PubMed=19246396; DOI=10.1073/pnas.0812642106;
RA   Zhong J., Gavrilescu L.C., Molnar A., Murray L., Garafalo S., Kehrl J.H.,
RA   Simon A.R., Van Etten R.A., Kyriakis J.M.;
RT   "GCK is essential to systemic inflammation and pattern recognition receptor
RT   signaling to JNK and p38.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:4372-4377(2009).
RN   [4]
RP   RETRACTION NOTICE OF PUBMED:19246396.
RX   PubMed=22411792; DOI=10.1073/pnas.1203538109;
RA   Gavrilescu L.C., Molnar A., Murray L., Garafalo S., Kehrl J.H., Simon A.R.,
RA   Van Etten R.A., Kyriakis J.M.;
RT   "Retraction for Zhong et al. GCK is essential to systemic inflammation and
RT   pattern recognition receptor signaling to JNK and p38.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:5134-5134(2012).
RN   [5]
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   [6]
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   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Kidney, Lung, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
CC   -!- FUNCTION: Serine/threonine-protein kinase which acts as an essential
CC       component of the MAP kinase signal transduction pathway
CC       (PubMed:8643544). Acts as a MAPK kinase kinase kinase (MAP4K) and is an
CC       upstream activator of the stress-activated protein kinase/c-Jun N-
CC       terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of
CC       the p38 MAPKs signaling pathway (By similarity). Required for the
CC       efficient activation of JNKs by TRAF6-dependent stimuli, including
CC       pathogen-associated molecular patterns (PAMPs) such as polyinosine-
CC       polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A,
CC       peptidoglycan (PGN), or bacterial flagellin (By similarity). To a
CC       lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-
CC       mediated JNKs activation (By similarity). The requirement for
CC       MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS
CC       stimulation of c-Jun phosphorylation and induction of IL-8 (By
CC       similarity). Enhances MAP3K1 oligomerization, which may relieve N-
CC       terminal mediated MAP3K1 autoinhibition and lead to activation
CC       following autophosphorylation (By similarity). Mediates also the
CC       SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through
CC       activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3 (By similarity).
CC       May play a role in the regulation of vesicle targeting or fusion (By
CC       similarity). {ECO:0000250|UniProtKB:Q12851,
CC       ECO:0000269|PubMed:8643544}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC         [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:8643544};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC         threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC         Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.1; Evidence={ECO:0000269|PubMed:8643544};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:8643544};
CC   -!- ACTIVITY REGULATION: The tumor necrosis factor (TNF), as well as
CC       endotoxins and pro-inflammatory 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 MAP3K11/MLK3 (By
CC       similarity). Interacts with RAB8A. {ECO:0000250,
CC       ECO:0000269|PubMed:8643544}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:8643544}.
CC       Basolateral cell membrane {ECO:0000269|PubMed:8643544}; Peripheral
CC       membrane protein {ECO:0000269|PubMed:8643544}. Golgi apparatus membrane
CC       {ECO:0000269|PubMed:8643544}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:8643544}.
CC   -!- DOMAIN: The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains.
CC       Proteins with PEST domains are frequently targets of degradation by the
CC       ubiquitin proteasome.
CC   -!- PTM: Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing
CC       proteasomal turnover. Ubiquitination requires the kinase activity of
CC       MAP4K2/GCK.
CC   -!- PTM: Autophosphorylated in response to tumor necrosis factor (TNF),
CC       endotoxins or pro-inflammatory stimuli. Autophosphorylation leads to
CC       activation.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC       protein kinase family. STE20 subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; U50595; AAC52571.1; -; mRNA.
DR   EMBL; AK051036; BAC34507.1; -; mRNA.
DR   CCDS; CCDS29503.1; -.
DR   RefSeq; NP_001278716.1; NM_001291787.1.
DR   RefSeq; NP_033032.1; NM_009006.3.
DR   AlphaFoldDB; Q61161; -.
DR   SMR; Q61161; -.
DR   BioGRID; 204965; 3.
DR   STRING; 10090.ENSMUSP00000025897; -.
DR   ChEMBL; CHEMBL4295856; -.
DR   GlyGen; Q61161; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q61161; -.
DR   PhosphoSitePlus; Q61161; -.
DR   EPD; Q61161; -.
DR   jPOST; Q61161; -.
DR   MaxQB; Q61161; -.
DR   PaxDb; 10090-ENSMUSP00000025897; -.
DR   ProteomicsDB; 295758; -.
DR   Pumba; Q61161; -.
DR   Antibodypedia; 2060; 284 antibodies from 28 providers.
DR   DNASU; 26412; -.
DR   Ensembl; ENSMUST00000025897.13; ENSMUSP00000025897.7; ENSMUSG00000024948.16.
DR   GeneID; 26412; -.
DR   KEGG; mmu:26412; -.
DR   UCSC; uc008gie.2; mouse.
DR   AGR; MGI:1346883; -.
DR   CTD; 5871; -.
DR   MGI; MGI:1346883; Map4k2.
DR   VEuPathDB; HostDB:ENSMUSG00000024948; -.
DR   eggNOG; KOG0576; Eukaryota.
DR   GeneTree; ENSGT00940000162250; -.
DR   HOGENOM; CLU_006347_1_1_1; -.
DR   InParanoid; Q61161; -.
DR   OMA; DTANNPE; -.
DR   OrthoDB; 152877at2759; -.
DR   PhylomeDB; Q61161; -.
DR   TreeFam; TF105121; -.
DR   BioGRID-ORCS; 26412; 2 hits in 79 CRISPR screens.
DR   PRO; PR:Q61161; -.
DR   Proteomes; UP000000589; Chromosome 19.
DR   RNAct; Q61161; Protein.
DR   Bgee; ENSMUSG00000024948; Expressed in granulocyte and 74 other cell types or tissues.
DR   ExpressionAtlas; Q61161; baseline and differential.
DR   GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR   GO; GO:0008349; F:MAP kinase kinase kinase kinase activity; IBA:GO_Central.
DR   GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; ISO:MGI.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR   GO; GO:0046330; P:positive regulation of JNK cascade; ISO:MGI.
DR   GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR   GO; GO:0006903; P:vesicle targeting; IDA:UniProtKB.
DR   CDD; cd06613; STKc_MAP4K3_like; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR001180; CNH_dom.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR021160; MAPKKKK.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   PANTHER; PTHR48012:SF6; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE 2; 1.
DR   PANTHER; PTHR48012; STERILE20-LIKE KINASE, ISOFORM B-RELATED; 1.
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; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS50219; CNH; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   Genevisible; Q61161; MM.
PE   1: Evidence at protein level;
KW   ATP-binding; Cell membrane; Cytoplasm; Golgi apparatus; Immunity;
KW   Innate immunity; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW   Reference proteome; Serine/threonine-protein kinase; Stress response;
KW   Transferase; Ubl conjugation.
FT   CHAIN           1..821
FT                   /note="Mitogen-activated protein kinase kinase kinase
FT                   kinase 2"
FT                   /id="PRO_0000086276"
FT   DOMAIN          16..273
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          483..794
FT                   /note="CNH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00795"
FT   REGION          294..314
FT                   /note="PEST1"
FT   REGION          344..360
FT                   /note="PEST2"
FT   REGION          405..449
FT                   /note="PEST3"
FT   REGION          409..442
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        413..429
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        136
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         22..30
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         45
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         328
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q12851"
FT   MOD_RES         394
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   CONFLICT        223
FT                   /note="L -> M (in Ref. 2; BAC34507)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   821 AA;  91265 MW;  2CCF750E45A53B05 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 RPTAERLLQH PFTTQHLPPA LLTQLLDKAS DPHLGTLSPE
     DSELETHDMF PDTIHSRSHH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG
     KEELSGSLLQ SVQEALEERS LTIRPALELQ ELDSPDDAIG TIKRAPFLGL PHTESTSGDN
     AQSCSPGTLS APPAGPGSPA LLPTAWATLK QQEDRERSSC HGLPPTPKVH MGACFSKVFN
     GCPLQIHAAV TWVHPVTRDQ FLVVGAEEGI YTLNLHELHE DTMEKLISQR CSWLYCVNNV
     LLSLSGKSTH IWAHDLPGLF EQRRLQHQAP LSIPTNRITQ RIIPRRFALS TKIPDTKGCL
     QCRVVRNPYT GSTFLLAALP ASLLLLQWYE PLQKFLLLKN FSSPLPSPAG MLEPLVLDGK
     ELPQVCVGAE GPEGPGCRVL FHVLPLEAGL TPDILIPPEG IPGSAQQVIQ VDRDTVLVSF
     ERCVRIVNLQ GEPTAALAPE LTFDFTIETV VCLQDSVLAF WSHGMQGRSL DTNEVTQEIT
     DETRIFRVLG AHRDIILESI PTDNPGAHSN LYILTGHQSS Y
//