ID M3K5_MOUSE Reviewed; 1380 AA. AC O35099; Q14AY5; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 3. DT 27-MAR-2024, entry version 198. DE RecName: Full=Mitogen-activated protein kinase kinase kinase 5; DE EC=2.7.11.25 {ECO:0000269|PubMed:16648474}; DE AltName: Full=Apoptosis signal-regulating kinase 1; DE Short=ASK-1; DE AltName: Full=MAPK/ERK kinase kinase 5; DE Short=MEK kinase 5; DE Short=MEKK 5; GN Name=Map3k5; Synonyms=Ask1, Mekk5; 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], AND TISSUE SPECIFICITY. RX PubMed=9367868; DOI=10.1006/bbrc.1997.7580; RA Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.; RT "Molecular cloning and characterization of the mouse apoptosis signal- RT regulating kinase 1."; RL Biochem. Biophys. Res. Commun. 239:905-910(1997). RN [2] RP SEQUENCE REVISION TO 22-26; 123; 273; 755; 1001-1011; 1220-1222 AND RP 1274-1280. RA Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP FUNCTION. RX PubMed=11266364; DOI=10.1093/embo-reports/kve046; RA Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., RA Minowa O., Miyazono K., Noda T., Ichijo H.; RT "ASK1 is required for sustained activations of JNK/p38 MAP kinases and RT apoptosis."; RL EMBO Rep. 2:222-228(2001). RN [5] RP PHOSPHORYLATION AT THR-845 AND THR-849, AND ACTIVITY REGULATION. RX PubMed=11920685; DOI=10.1002/jcp.10080; RA Tobiume K., Saitoh M., Ichijo H.; RT "Activation of apoptosis signal-regulating kinase 1 by the stress-induced RT activating phosphorylation of pre-formed oligomer."; RL J. Cell. Physiol. 191:95-104(2002). RN [6] RP FUNCTION. RX PubMed=14749717; DOI=10.1038/sj.embor.7400072; RA Takeda K., Matsuzawa A., Nishitoh H., Tobiume K., Kishida S., RA Ninomiya-Tsuji J., Matsumoto K., Ichijo H.; RT "Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation."; RL EMBO Rep. 5:161-166(2004). RN [7] RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH TRAF6. RX PubMed=15864310; DOI=10.1038/ni1200; RA Matsuzawa A., Saegusa K., Noguchi T., Sadamitsu C., Nishitoh H., Nagai S., RA Koyasu S., Matsumoto K., Takeda K., Ichijo H.; RT "ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively RT required for TLR4-mediated innate immunity."; RL Nat. Immunol. 6:587-592(2005). RN [8] RP FUNCTION. RX PubMed=16527894; DOI=10.1182/blood-2005-09-3866; RA Rubiolo C., Piazzolla D., Meissl K., Beug H., Huber J.C., Kolbus A., RA Baccarini M.; RT "A balance between Raf-1 and Fas expression sets the pace of erythroid RT differentiation."; RL Blood 108:152-159(2006). RN [9] RP INTERACTION WITH PPP3R1, PHOSPHORYLATION AT SER-973, ACTIVITY REGULATION, RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16648474; DOI=10.1128/mcb.26.10.3785-3797.2006; RA Liu Q., Wilkins B.J., Lee Y.J., Ichijo H., Molkentin J.D.; RT "Direct interaction and reciprocal regulation between ASK1 and calcineurin- RT NFAT control cardiomyocyte death and growth."; RL Mol. Cell. Biol. 26:3785-3797(2006). RN [10] RP INTERACTION WITH PPM1L. RX PubMed=17456047; DOI=10.1042/bj20070231; RA Saito J., Toriumi S., Awano K., Ichijo H., Sasaki K., Kobayashi T., RA Tamura S.; RT "Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase RT 2Cepsilon."; RL Biochem. J. 405:591-596(2007). RN [11] RP PHOSPHORYLATION AT THR-845. RX PubMed=18948261; DOI=10.1074/jbc.m807219200; RA Jung H., Seong H.A., Ha H.; RT "Murine protein serine/threonine kinase 38 activates apoptosis signal- RT regulating kinase 1 via Thr 838 phosphorylation."; RL J. Biol. Chem. 283:34541-34553(2008). RN [12] RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION. RX PubMed=17883330; DOI=10.1146/annurev.pharmtox.48.113006.094606; RA Takeda K., Noguchi T., Naguro I., Ichijo H.; RT "Apoptosis signal-regulating kinase 1 in stress and immune response."; RL Annu. Rev. Pharmacol. Toxicol. 48:199-225(2008). RN [13] RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION. RX PubMed=19389260; DOI=10.1186/1478-811x-7-9; RA Hattori K., Naguro I., Runchel C., Ichijo H.; RT "The roles of ASK family proteins in stress responses and diseases."; RL Cell Commun. Signal. 7:9-9(2009). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Lung, Pancreas, and Spleen; 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 [15] RP INTERACTION WITH PPP5C, PHOSPHORYLATION AT THR-845, AND DEPHOSPHORYLATION RP AT THR-845 BY PPP5C. RX PubMed=22399290; DOI=10.1074/jbc.m111.329771; RA Yamaguchi F., Umeda Y., Shimamoto S., Tsuchiya M., Tokumitsu H., Tokuda M., RA Kobayashi R.; RT "S100 proteins modulate protein phosphatase 5 function: a link between CA2+ RT signal transduction and protein dephosphorylation."; RL J. Biol. Chem. 287:13787-13798(2012). CC -!- FUNCTION: Serine/threonine kinase which acts as an essential component CC of the MAP kinase signal transduction pathway. Plays an important role CC in the cascades of cellular responses evoked by changes in the CC environment. Mediates signaling for determination of cell fate such as CC differentiation and survival. Plays a crucial role in the apoptosis CC signal transduction pathway through mitochondria-dependent caspase CC activation. MAP3K5/ASK1 is required for the innate immune response, CC which is essential for host defense against a wide range of pathogens. CC Mediates signal transduction of various stressors like oxidative stress CC as well as by receptor-mediated inflammatory signals, such as the tumor CC necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts CC as an upstream activator of the MKK/JNK signal transduction cascade and CC the p38 MAPK signal transduction cascade through the phosphorylation CC and activation of several MAP kinase kinases like MAP2K4/SEK1, CC MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate CC p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs CC control the transcription factors activator protein-1 (AP-1). CC {ECO:0000269|PubMed:11266364, ECO:0000269|PubMed:14749717, CC ECO:0000269|PubMed:15864310, ECO:0000269|PubMed:16527894, CC ECO:0000269|PubMed:16648474}. 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=2.7.11.25; CC Evidence={ECO:0000269|PubMed:16648474}; 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=2.7.11.25; Evidence={ECO:0000269|PubMed:16648474}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250}; CC -!- ACTIVITY REGULATION: Activated by various stressors, including CC oxidative stress, endoplasmic reticulum stress, and calcium overload, CC as well as by receptor-mediated inflammatory signals, such as the tumor CC necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic CC association of MAP3K5/ASK1 through the C-terminal coiled-coil domains CC and the heteromeric complex formation of MAP3K5/ASK1 with the reduced CC form of thioredoxin (TXN), constitutes an inactive form of the kinase. CC Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 CC are reciprocally recruited to MAP3K5/ASK1 and form the active CC MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate CC the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also CC regulated through several phosphorylation and dephosphorylation events. CC Thr-845 is an activating phosphorylation site that is CC autophosphorylated and phosphorylated by MAP3K6/ASK2 and CC dephosphorylated by PPP5C. Ser-90 and Ser-1040 are inactivating CC phosphorylation sites, the former of which is phosphorylated by AKT1. CC Phosphorylation of Ser-973 induces association of MAP3K5/ASK1 with the CC 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. CC Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) CC has been shown to directly dephosphorylate this site. SOCS1 binds to CC ASK1 by recognizing phosphorylation of Tyr-725 and induces MAP3K5/ASK1 CC degradation in endothelial cells. Also dephosphorylated and activated CC by PGAM5. Contains an N-terminal autoinhibitory domain. CC {ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:15864310, CC ECO:0000269|PubMed:16648474}. CC -!- SUBUNIT: Homodimer when inactive (By similarity). Binds both upstream CC activators and downstream substrates in multimolecular complexes. Part CC of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response CC to TNF (By similarity). This complex formation promotes MAP3K5-JNK CC activation and subsequent apoptosis (By similarity). Interacts with CC SOCS1 which recognizes phosphorylation of Tyr-725 and induces CC MAP3K5/ASK1 degradation in endothelial cells (By similarity). Interacts CC with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, CC YWHAZ and SFN (By similarity). Interacts with ARRB2, BIRC2, DAB2IP, CC IGF1R, MAP3K6/ASK2, PIM1, PGAM5, SOCS1, STUB1, TRAF2 and TXN (By CC similarity). Interacts with ERN1 in a TRAF2-dependent manner (By CC similarity). Interacts with calcineurin subunit PPP3R1, PPP5C, PPM1L CC and TRAF6 (PubMed:15864310, PubMed:16648474, PubMed:17456047, CC PubMed:22399290). Interacts (via N-terminus) with RAF1 and this CC interaction inhibits the proapoptotic function of MAP3K5. Interacts CC with DAB2IP (via N-terminus C2 domain); the interaction occurs in a CC TNF-alpha-dependent manner (By similarity).Interacts with DUSP13A; may CC positively regulate apoptosis (By similarity). Interacts with PPIA/CYPA CC (By similarity). Interacts with PRMT1; the interaction results in CC MAP3K5 methylation by PRMT1 which inhibits MAP3K5 activation (By CC similarity). Interacts with TRAF2; the interaction is inhibited by CC PRMT1 (By similarity). Interacts with TRIM48 (By similarity). CC {ECO:0000250|UniProtKB:Q99683, ECO:0000269|PubMed:15864310, CC ECO:0000269|PubMed:16648474, ECO:0000269|PubMed:17456047, CC ECO:0000269|PubMed:22399290}. CC -!- INTERACTION: CC O35099; Q63810: Ppp3r1; NbExp=3; IntAct=EBI-777493, EBI-6666164; CC O35099; Q9D1C8: Vps28; NbExp=3; IntAct=EBI-777493, EBI-309205; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q99683}. CC Endoplasmic reticulum {ECO:0000250}. Note=Interaction with 14-3-3 CC proteins alters the distribution of MAP3K5/ASK1 and restricts it to the CC perinuclear endoplasmic reticulum region. {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in various adult mouse tissues including CC heart, brain, lung, liver and kidney. {ECO:0000269|PubMed:9367868}. CC -!- PTM: Ser-90 and Ser-1040 are inactivating phosphorylation sites, the CC former of which is phosphorylated by AKT1 (By similarity). CC Phosphorylated at Ser-973 which induces association of MAP3K5/ASK1 with CC the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity CC (PubMed:16648474). Calcineurin (CN) dephosphorylates this site. Also CC dephosphorylated and activated by PGAM5 (By similarity). Phosphorylated CC at Thr-845 through autophosphorylation and by MAP3K6/ASK2 which leads CC to activation (PubMed:11920685, PubMed:18948261, PubMed:22399290). Thr- CC 845 is dephosphorylated by PPP5C (PubMed:22399290). Phosphorylation at CC Ser-973 in response to oxidative stress is negatively regulated by CC PPIA/CYPA (By similarity). {ECO:0000250|UniProtKB:Q99683, CC ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:16648474, CC ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:22399290}. CC -!- PTM: Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2-dependent CC ubiquitination, leading to proteasomal degradation. Ubiquitinated by CC RC3H2 in a TRIM48-dependent manner. {ECO:0000250|UniProtKB:Q99683}. CC -!- PTM: Methylation at Arg-85 and Arg-87 by PRMT1 promotes association of CC MAP3K5 with thioredoxin and negatively regulates MAP3K5 association CC with TRAF2, inhibiting MAP3K5 activation. Methylation is blocked by CC ubiquitination of PRMT1 by TRIM48. {ECO:0000250|UniProtKB:Q99683}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr CC protein kinase family. MAP kinase kinase kinase subfamily. CC {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; AB006787; BAA23648.3; -; mRNA. DR EMBL; BC116627; AAI16628.1; -; mRNA. DR EMBL; BC133697; AAI33698.1; -; mRNA. DR CCDS; CCDS35857.1; -. DR PIR; JC5778; JC5778. DR RefSeq; NP_032606.4; NM_008580.4. DR AlphaFoldDB; O35099; -. DR SMR; O35099; -. DR BioGRID; 204961; 24. DR CORUM; O35099; -. DR DIP; DIP-38055N; -. DR IntAct; O35099; 15. DR MINT; O35099; -. DR STRING; 10090.ENSMUSP00000093485; -. DR ChEMBL; CHEMBL4879411; -. DR GlyGen; O35099; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; O35099; -. DR PhosphoSitePlus; O35099; -. DR EPD; O35099; -. DR jPOST; O35099; -. DR MaxQB; O35099; -. DR PaxDb; 10090-ENSMUSP00000093485; -. DR ProteomicsDB; 252700; -. DR Antibodypedia; 3592; 1776 antibodies from 44 providers. DR DNASU; 26408; -. DR Ensembl; ENSMUST00000095806.10; ENSMUSP00000093485.4; ENSMUSG00000071369.12. DR GeneID; 26408; -. DR KEGG; mmu:26408; -. DR UCSC; uc007enm.2; mouse. DR AGR; MGI:1346876; -. DR CTD; 4217; -. DR MGI; MGI:1346876; Map3k5. DR VEuPathDB; HostDB:ENSMUSG00000071369; -. DR eggNOG; KOG4279; Eukaryota. DR GeneTree; ENSGT00940000159155; -. DR InParanoid; O35099; -. DR OMA; ICLAHSK; -. DR OrthoDB; 5388799at2759; -. DR PhylomeDB; O35099; -. DR TreeFam; TF105115; -. DR BRENDA; 2.7.12.2; 3474. DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence. DR BioGRID-ORCS; 26408; 3 hits in 80 CRISPR screens. DR ChiTaRS; Map3k5; mouse. DR PRO; PR:O35099; -. DR Proteomes; UP000000589; Chromosome 10. DR RNAct; O35099; Protein. DR Bgee; ENSMUSG00000071369; Expressed in ciliary body and 267 other cell types or tissues. DR ExpressionAtlas; O35099; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0009897; C:external side of plasma membrane; ISO:MGI. DR GO; GO:1990604; C:IRE1-TRAF2-ASK1 complex; ISO:MGI. DR GO; GO:1902911; C:protein kinase complex; ISO:MGI. DR GO; GO:0032991; C:protein-containing complex; ISO:MGI. DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0004706; F:JUN kinase kinase kinase activity; ISO:MGI. DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:UniProtKB. DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI. DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; ISO:MGI. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0034198; P:cellular response to amino acid starvation; ISO:MGI. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:MGI. DR GO; GO:1902170; P:cellular response to reactive nitrogen species; IMP:MGI. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl. DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; IDA:MGI. DR GO; GO:0007254; P:JNK cascade; ISS:UniProtKB. DR GO; GO:0000165; P:MAPK cascade; ISS:UniProtKB. DR GO; GO:0051402; P:neuron apoptotic process; IMP:ParkinsonsUK-UCL. DR GO; GO:0036480; P:neuron intrinsic apoptotic signaling pathway in response to oxidative stress; ISO:MGI. DR GO; GO:0038066; P:p38MAPK cascade; IEP:CACAO. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; ISO:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:MGI. DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:ParkinsonsUK-UCL. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI. DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IDA:CACAO. DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISO:MGI. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI. DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:MGI. DR GO; GO:0097300; P:programmed necrotic cell death; IMP:MGI. DR GO; GO:0043067; P:regulation of programmed cell death; IGI:MGI. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0051403; P:stress-activated MAPK cascade; ISO:MGI. DR CDD; cd06624; STKc_ASK; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR046872; DRHyd-ASK. DR InterPro; IPR046873; HisK-N-like. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR043969; MAP3K_PH. DR InterPro; IPR025136; MAP3K_TRAF-bd. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR013761; SAM/pointed_sf. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR11584:SF332; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5; 1. DR PANTHER; PTHR11584; SERINE/THREONINE PROTEIN KINASE; 1. DR Pfam; PF19039; ASK_PH; 1. DR Pfam; PF20309; DRHyd-ASK; 1. DR Pfam; PF20302; HisK-N-like; 1. DR Pfam; PF13281; MAP3K_TRAF_bd; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF47769; SAM/Pointed domain; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; O35099; MM. PE 1: Evidence at protein level; KW Apoptosis; ATP-binding; Coiled coil; Cytoplasm; Endoplasmic reticulum; KW Immunity; Innate immunity; Kinase; Magnesium; Metal-binding; Methylation; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Stress response; Transferase; KW Ubl conjugation. FT CHAIN 1..1380 FT /note="Mitogen-activated protein kinase kinase kinase 5" FT /id="PRO_0000086250" FT DOMAIN 687..945 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 30..97 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 649..1374 FT /note="Interaction with PPIA/CYPA" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT REGION 1188..1215 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 1252..1292 FT /evidence="ECO:0000255" FT COMPBIAS 47..61 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 66..97 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 810 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 693..701 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 716 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 85 FT /note="Asymmetric dimethylarginine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 87 FT /note="Asymmetric dimethylarginine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 90 FT /note="Phosphoserine; by PIM1 and PKB/AKT1" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 725 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 820 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 845 FT /note="Phosphothreonine; by autocatalysis, MELK and MAP3K6" FT /evidence="ECO:0000269|PubMed:11920685, FT ECO:0000269|PubMed:18948261, ECO:0000269|PubMed:22399290" FT MOD_RES 849 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:11920685" FT MOD_RES 965 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 973 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16648474" FT MOD_RES 1036 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT MOD_RES 1040 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q99683" FT CONFLICT 166 FT /note="A -> T (in Ref. 1; BAA23648)" FT /evidence="ECO:0000305" FT CONFLICT 368..370 FT /note="RRN -> TRT (in Ref. 1; BAA23648)" FT /evidence="ECO:0000305" FT CONFLICT 1090 FT /note="K -> N (in Ref. 1; BAA23648)" FT /evidence="ECO:0000305" SQ SEQUENCE 1380 AA; 154512 MW; BE68D225EBBCDF38 CRC64; MGTEAGEGIT FSVPPFASVG FCTIPEGGSC RRGGGAATAA EGEPSLQPLL VPPPPPPPGS FWNVESAAAP GTSCPTTAPG SSATRGRGNS GSGGGRRTTV AYVINEASQG QLVVAESEAL QSLREACEAV GATLETLHFG KLDFGETAVL DRFYNADIAV VEMSDAFRQP SLFYHLGVRE SFSMANNIIL YCDTNSDSLQ SLKEIICQKN TVCTGNYTFI PYMVTPHNKV YCCDSSFMKG LTELMQPNFE LLLGPICLPL VDRFVQLLKV AQASSSQYFR ESILSDIRKA RNLYTGKELA AELARIRQRV DNIEVLTADI VINLLLSYRD IQDYDSIVKL VETLEKLPTF DLASHHHVKF HYAFALNRRN LPGDRAKALD IMIPMVQSEE QVASDMYCLV GRIYKDMFLD SNFTDTESRD HGASWFKKAF ESEPTLQSGI NYAVLLLAAG HQFESSFELR KVGVKLSSLL GKKGNLEKLQ SYWEVGFFLG ASVLANDHLR VIQASEKLFR LKTPAWYLKS IVETILIYKH FVKLTTEQPS AKQELVDFWM DFLVEATKTD VTVVRFPVLI LEPTKIYQPS YLSINNEVEE KTISIWHVLP DDKKGIHEWN FGASSVRGVS ISKFEERCCF LYVLHNSDDF QIYFCTELHC KRFFEMVNTI TEEKGRGAED GDCEGDSLEY DYEYDENGDR VVLGKGTYGI VYAGRDLSNQ VRIAIKEIPE RDSRYSQPLH EEIALHKHLK HKNIVQYLGS FSENGFIKIF MEQVPGGSLS ALLRSKWGPL KDNEQTIGFY TKQILEGLKY LHDNQIVHRD IKGDNVLINT YSGVLKISDF GTSKRLAGIN PCTETFTGTL QYMAPEIIDK GPRGYGKAAD IWSLGCTIIE MATGKPPFYE LGEPQAAMFK VGMFKVHPEI PESMSAEAKA FILKCFEPDP DKRACANDLL IDEFLKVSSK KKKTQPKLSA LSTGSNEYLR SISLPVPVLV EDTSSSSEYG SVSPDTELKA DPFSFKARAK SCGEKDGKGI RTLFLGIPDE NFEDHSAPPS PEEKDSGFFM LRKDSERRAT LHRILTEDQD KVVRNLMESL AQGAEEPKLK WEHITTLISS LREFVRSTDR KIIATTLSKL KLELDFDSHG ISQVQVVLFG FQDAVNKVLR NHNIKPHWMF ALDSIIRKAV QTAITILVPE LRPHFSLASE SDTADPEDLD VEDEHEELSS NQTVRRPQAI TEDAVATSGV STLSSTVSHD SQNAHRSLNV QLGRMKIETN RLLEELVRKE RELQALLHQA IEEKDQEIRH LKLKSQPIDI PGFPVCHLNS PGTTTEDSEL PGWLRENGAD EDTISRFLAE DYTLVDVLYY VTRDDLKCLR LRGGMLCTLW KAIIDFRNKC //