MP2K4_MOUSE
ID MP2K4_MOUSE Reviewed; 397 AA.
AC P47809;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 2.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4;
DE Short=MAP kinase kinase 4;
DE Short=MAPKK 4;
DE EC=2.7.12.2;
DE AltName: Full=C-JUN N-terminal kinase kinase 1;
DE Short=JNK kinase 1;
DE Short=JNKK 1;
DE AltName: Full=JNK-activating kinase 1;
DE AltName: Full=MAPK/ERK kinase 4;
DE Short=MEK 4;
DE AltName: Full=SAPK/ERK kinase 1;
DE Short=SEK1;
GN Name=Map2k4; Synonyms=Jnkk1, Mek4, Mkk4, Prkmk4, Sek1, Serk1, Skk1;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND MUTAGENESIS OF LYS-129.
RC TISSUE=Embryo;
RX PubMed=7997269; DOI=10.1038/372794a0;
RA Sanchez I., Hughes R.T., Mayer B.J., Yee K., Woodgett J.R., Avruch J.,
RA Kyriakis J.M., Zon L.I.;
RT "Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating
RT transcription factor c-Jun.";
RL Nature 372:794-798(1994).
RN [2]
RP SEQUENCE REVISION.
RA Zon L.I.;
RL Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION.
RX PubMed=9620683; DOI=10.1016/s1074-7613(00)80567-1;
RA Swat W., Fujikawa K., Ganiatsas S., Yang D., Xavier R.J., Harris N.L.,
RA Davidson L., Ferrini R., Davis R.J., Labow M.A., Flavell R.A., Zon L.I.,
RA Alt F.W.;
RT "SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid
RT compartment but not for lymphocyte development.";
RL Immunity 8:625-634(1998).
RN [4]
RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND FUNCTION OF THE MKK/JNK
RP PATHWAY.
RX PubMed=9891090; DOI=10.1128/mcb.19.2.1569;
RA Tournier C., Whitmarsh A.J., Cavanagh J., Barrett T., Davis R.J.;
RT "The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases.";
RL Mol. Cell. Biol. 19:1569-1581(1999).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=10095085; DOI=10.1016/s0169-328x(99)00035-2;
RA Lee J.K., Hwang W.S., Lee Y.D., Han P.L.;
RT "Dynamic expression of SEK1 suggests multiple roles of the gene during
RT embryogenesis and in adult brain of mice.";
RL Brain Res. Mol. Brain Res. 66:133-140(1999).
RN [6]
RP FUNCTION.
RX PubMed=11390361; DOI=10.1101/gad.888501;
RA Tournier C., Dong C., Turner T.K., Jones S.N., Flavell R.A., Davis R.J.;
RT "MKK7 is an essential component of the JNK signal transduction pathway
RT activated by proinflammatory cytokines.";
RL Genes Dev. 15:1419-1426(2001).
RN [7]
RP PHOSPHORYLATION, AND INTERACTION WITH MAP3K1/MEKK1.
RX PubMed=12401521; DOI=10.1016/s0898-6568(02)00056-6;
RA Tu Z., Mooney S.M., Lee F.S.;
RT "A subdomain of MEKK1 that is critical for binding to MKK4.";
RL Cell. Signal. 15:65-77(2003).
RN [8]
RP FUNCTION.
RX PubMed=12624093; DOI=10.1074/jbc.m213182200;
RA Kishimoto H., Nakagawa K., Watanabe T., Kitagawa D., Momose H., Seo J.,
RA Nishitai G., Shimizu N., Ohata S., Tanemura S., Asaka S., Goto T.,
RA Fukushi H., Yoshida H., Suzuki A., Sasaki T., Wada T., Penninger J.M.,
RA Nishina H., Katada T.;
RT "Different properties of SEK1 and MKK7 in dual phosphorylation of stress-
RT induced activated protein kinase SAPK/JNK in embryonic stem cells.";
RL J. Biol. Chem. 278:16595-16601(2003).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=17875933; DOI=10.1128/mcb.00226-07;
RA Wang X., Nadarajah B., Robinson A.C., McColl B.W., Jin J.W.,
RA Dajas-Bailador F., Boot-Handford R.P., Tournier C.;
RT "Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in
RT the nervous system causes severe brain developmental defects and premature
RT death.";
RL Mol. Cell. Biol. 27:7935-7946(2007).
RN [10]
RP DISRUPTION PHENOTYPE.
RX PubMed=19265040; DOI=10.1161/circresaha.108.188292;
RA Liu W., Zi M., Jin J., Prehar S., Oceandy D., Kimura T.E., Lei M.,
RA Neyses L., Weston A.H., Cartwright E.J., Wang X.;
RT "Cardiac-specific deletion of mkk4 reveals its role in pathological
RT hypertrophic remodeling but not in physiological cardiac growth.";
RL Circ. Res. 104:905-914(2009).
RN [11]
RP REVIEW ON ACTIVITY REGULATION.
RX PubMed=17496909; DOI=10.1038/sj.onc.1210392;
RA Raman M., Chen W., Cobb M.H.;
RT "Differential regulation and properties of MAPKs.";
RL Oncogene 26:3100-3112(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-255 AND THR-259, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC 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).
RN [13]
RP REVIEW ON FUNCTION.
RX PubMed=20801953; DOI=10.1093/jb/mvq098;
RA Asaoka Y., Nishina H.;
RT "Diverse physiological functions of MKK4 and MKK7 during early
RT embryogenesis.";
RL J. Biochem. 148:393-401(2010).
RN [14]
RP REVIEW ON REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21333379; DOI=10.1016/j.ejcb.2010.11.008;
RA Haeusgen W., Herdegen T., Waetzig V.;
RT "The bottleneck of JNK signaling: molecular and functional characteristics
RT of MKK4 and MKK7.";
RL Eur. J. Cell Biol. 90:536-544(2011).
RN [15]
RP INTERACTION WITH SPAG9.
RX PubMed=12391307; DOI=10.1073/pnas.232310199;
RA Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P.;
RT "JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and
RT transcription factors.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002).
RN [16]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-56, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. Essential
CC component of the stress-activated protein kinase/c-Jun N-terminal
CC kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the
CC only known kinase to directly activate the stress-activated protein
CC kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3.
CC MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation,
CC but they differ in their preference for the phosphorylation site in the
CC Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the
CC Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of
CC the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK
CC activation at least in response to pro-inflammatory cytokines, while
CC other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which
CC synergistically phosphorylate JNKs. MAP2K4 is required for maintaining
CC peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also
CC involved in mitochondrial death signaling pathway, including the
CC release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7
CC exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38
CC MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. {ECO:0000269|PubMed:11390361,
CC ECO:0000269|PubMed:12624093, ECO:0000269|PubMed:7997269,
CC ECO:0000269|PubMed:9620683, ECO:0000269|PubMed:9891090}.
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=2.7.12.2;
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=2.7.12.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC -!- ACTIVITY REGULATION: Activated in response to a variety of cellular
CC stresses, including UV and gamma-irradiation, heat shock,
CC hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory
CC cytokines. Also activated by developmental cues. MAP2K4/MKK4 is
CC activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
CC {ECO:0000269|PubMed:9891090}.
CC -!- SUBUNIT: Interacts with SPAG9. Interacts (via its D domain) with its
CC substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 (By
CC similarity). Interacts (via its DVD domain) with MAP3Ks activators like
CC MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and
CC MAPK8IP3/JIP3 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P47809; P53349: Map3k1; NbExp=2; IntAct=EBI-447934, EBI-447913;
CC P47809; Q9ESN9-2: Mapk8ip3; NbExp=3; IntAct=EBI-447934, EBI-9549291;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9891090}. Nucleus
CC {ECO:0000269|PubMed:9891090}.
CC -!- TISSUE SPECIFICITY: Strong expression is detected in most of the
CC central nervous system and in liver and thymus during early stages of
CC development. While expression in nervous system increases over time,
CC expression in fetal liver and thymus gradually decreases as
CC embryogenesis proceeds. High level of expression in the central nervous
CC system persists throughout postnatal development and remained at a
CC stable level in adult brain. {ECO:0000269|PubMed:10095085}.
CC -!- DOMAIN: The DVD domain (residues 362-385) contains a conserved docking
CC site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD
CC sites bind to their specific upstream MAP kinase kinase kinases
CC (MAP3Ks) and are essential for activation (By similarity).
CC {ECO:0000250}.
CC -!- DOMAIN: The D domain (residues 35-50) contains a conserved docking site
CC and is required for the binding to MAPk substrates.
CC -!- PTM: Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase
CC kinase kinases (MAP3Ks). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Causes irregular alignment of Purkinje cells in
CC the cerebellum and delayed radial migration in the cortex during brain
CC development. The cardiac-specific deletion prevents pathological
CC cardiac hypertrophy. {ECO:0000269|PubMed:17875933,
CC ECO:0000269|PubMed:19265040}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase 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; U18310; AAB81554.1; -; mRNA.
DR CCDS; CCDS24844.1; -.
DR PIR; S52423; S52423.
DR RefSeq; NP_033183.1; NM_009157.5.
DR AlphaFoldDB; P47809; -.
DR SMR; P47809; -.
DR BioGRID; 204952; 17.
DR CORUM; P47809; -.
DR DIP; DIP-869N; -.
DR IntAct; P47809; 4.
DR STRING; 10090.ENSMUSP00000041282; -.
DR ChEMBL; CHEMBL2201; -.
DR iPTMnet; P47809; -.
DR PhosphoSitePlus; P47809; -.
DR EPD; P47809; -.
DR jPOST; P47809; -.
DR PaxDb; P47809; -.
DR PeptideAtlas; P47809; -.
DR PRIDE; P47809; -.
DR ProteomicsDB; 295582; -.
DR Antibodypedia; 3571; 1436 antibodies from 42 providers.
DR DNASU; 26398; -.
DR Ensembl; ENSMUST00000046963; ENSMUSP00000041282; ENSMUSG00000033352.
DR GeneID; 26398; -.
DR KEGG; mmu:26398; -.
DR UCSC; uc007jlb.1; mouse.
DR CTD; 6416; -.
DR MGI; MGI:1346869; Map2k4.
DR VEuPathDB; HostDB:ENSMUSG00000033352; -.
DR eggNOG; KOG1006; Eukaryota.
DR GeneTree; ENSGT00940000154744; -.
DR HOGENOM; CLU_000288_63_23_1; -.
DR InParanoid; P47809; -.
DR OMA; REAPLCC; -.
DR PhylomeDB; P47809; -.
DR TreeFam; TF350701; -.
DR BRENDA; 2.7.12.2; 3474.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-2871796; FCERI mediated MAPK activation.
DR Reactome; R-MMU-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR BioGRID-ORCS; 26398; 6 hits in 74 CRISPR screens.
DR ChiTaRS; Map2k4; mouse.
DR PRO; PR:P47809; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; P47809; protein.
DR Bgee; ENSMUSG00000033352; Expressed in dentate gyrus of hippocampal formation granule cell and 284 other tissues.
DR ExpressionAtlas; P47809; baseline and differential.
DR Genevisible; P47809; MM.
DR GO; GO:0030424; C:axon; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0032839; C:dendrite cytoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0043204; C:perikaryon; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008545; F:JUN kinase kinase activity; ISO:MGI.
DR GO; GO:0004708; F:MAP kinase kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0061049; P:cell growth involved in cardiac muscle cell development; ISO:MGI.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; ISO:MGI.
DR GO; GO:0000165; P:MAPK cascade; IPI:MGI.
DR GO; GO:2000672; P:negative regulation of motor neuron apoptotic process; IMP:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0045740; P:positive regulation of DNA replication; ISO:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:MGI.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISO:MGI.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0009611; P:response to wounding; IMP:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; ATP-binding; Cytoplasm; Kinase; Methylation;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P45985"
FT CHAIN 2..397
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 4"
FT /id="PRO_0000086382"
FT DOMAIN 100..366
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 35..50
FT /note="D domain"
FT /evidence="ECO:0000250"
FT REGION 362..385
FT /note="DVD domain"
FT /evidence="ECO:0000250"
FT ACT_SITE 227
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 106..114
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 129
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P45985"
FT MOD_RES 56
FT /note="Asymmetric dimethylarginine; alternate"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 56
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P45985"
FT MOD_RES 88
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 255
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 259
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 129
FT /note="K->R: Loss of ATP-binding."
FT /evidence="ECO:0000269|PubMed:7997269"
SQ SEQUENCE 397 AA; 44114 MW; B99C6688184E5B3D CRC64;
MAAPSPSGGG GSGGGGGTPG PIGPPASGHP AVSSMQGKRK ALKLNFANPP VKSTARFTLN
PNTTGVQNPH IERLRTHSIE SSGKLKISPE QHWDFTAEDL KDLGEIGRGA YGSVNKMVHK
PSGQIMAVKR IRSTVDEKEQ KQLLMDLDVV MRSSDCPYIV QFYGALFREG DCWICMELMS
TSFDKFYKYV YSVLDDVIPE EILGKITLAT VKALNHLKEN LKIIHRDIKP SNILLDRSGN
IKLCDFGISG QLVDSIAKTR DAGCRPYMAP ERIDPSASRQ GYDVRSDVWS LGITLYELAT
GRFPYPKWNS VFDQLTQVVK GDPPQLSNSE EREFSPSFIN FVNLCLTKDE SKRPKYKELL
KHPFILMYEE RTVEVACYVC KILDQMPATP SSPMYVD
