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 27-MAR-2024, entry version 187. 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, RC Pancreas, 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; 18. DR CORUM; P47809; -. DR DIP; DIP-869N; -. DR IntAct; P47809; 4. DR STRING; 10090.ENSMUSP00000041282; -. DR BindingDB; P47809; -. DR ChEMBL; CHEMBL2201; -. DR GlyGen; P47809; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P47809; -. DR PhosphoSitePlus; P47809; -. DR SwissPalm; P47809; -. DR EPD; P47809; -. DR jPOST; P47809; -. DR PaxDb; 10090-ENSMUSP00000041282; -. DR PeptideAtlas; P47809; -. DR ProteomicsDB; 295582; -. DR Pumba; P47809; -. DR Antibodypedia; 3571; 1597 antibodies from 42 providers. DR DNASU; 26398; -. DR Ensembl; ENSMUST00000046963.10; ENSMUSP00000041282.4; ENSMUSG00000033352.12. DR GeneID; 26398; -. DR KEGG; mmu:26398; -. DR UCSC; uc007jlb.1; mouse. DR AGR; MGI:1346869; -. 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; FIGRCLK; -. DR OrthoDB; 2900742at2759; -. 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; 7 hits in 79 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 287 other cell types or tissues. DR ExpressionAtlas; P47809; baseline and differential. DR GO; GO:0030424; C:axon; ISO:MGI. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0032839; C:dendrite cytoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. 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:0060090; F:molecular adaptor 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: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:0036481; P:intrinsic apoptotic signaling pathway in response to hydrogen peroxide; IDA:BHF-UCL. 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:0016310; P:phosphorylation; IEA:UniProtKB-KW. 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: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:0009611; P:response to wounding; IMP:MGI. DR GO; GO:0034390; P:smooth muscle cell apoptotic process; IDA:BHF-UCL. DR CDD; cd06616; PKc_MKK4; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR48013:SF35; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4; 1. DR PANTHER; PTHR48013; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 5-RELATED; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P47809; MM. 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 //