M3K5_MOUSE
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 03-AUG-2022, entry version 189.
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
CC DUSP13/DUSP13A; may positively regulate apoptosis (By similarity).
CC Interacts with PPIA/CYPA (By similarity). Interacts with PRMT1; the
CC interaction results in MAP3K5 methylation by PRMT1 which inhibits
CC MAP3K5 activation (By similarity). Interacts with TRAF2; the
CC interaction is inhibited by PRMT1 (By similarity). Interacts with
CC TRIM48 (By similarity). {ECO:0000250|UniProtKB:Q99683,
CC ECO:0000269|PubMed:15864310, ECO:0000269|PubMed:16648474,
CC ECO:0000269|PubMed:17456047, 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}.
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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; 22.
DR CORUM; O35099; -.
DR DIP; DIP-38055N; -.
DR IntAct; O35099; 15.
DR MINT; O35099; -.
DR STRING; 10090.ENSMUSP00000093485; -.
DR iPTMnet; O35099; -.
DR PhosphoSitePlus; O35099; -.
DR EPD; O35099; -.
DR jPOST; O35099; -.
DR MaxQB; O35099; -.
DR PaxDb; O35099; -.
DR PRIDE; O35099; -.
DR ProteomicsDB; 252700; -.
DR Antibodypedia; 3592; 1586 antibodies from 44 providers.
DR DNASU; 26408; -.
DR Ensembl; ENSMUST00000095806; ENSMUSP00000093485; ENSMUSG00000071369.
DR GeneID; 26408; -.
DR KEGG; mmu:26408; -.
DR UCSC; uc007enm.2; mouse.
DR CTD; 4217; -.
DR MGI; MGI:1346876; Map3k5.
DR VEuPathDB; HostDB:ENSMUSG00000071369; -.
DR eggNOG; KOG4279; Eukaryota.
DR GeneTree; ENSGT00940000159155; -.
DR InParanoid; O35099; -.
DR OMA; ETNSCHL; -.
DR OrthoDB; 226722at2759; -.
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 75 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 264 other tissues.
DR ExpressionAtlas; O35099; baseline and differential.
DR Genevisible; O35099; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
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:0038066; P:p38MAPK cascade; IEP:CACAO.
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; IEA:Ensembl.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:ParkinsonsUK-UCL.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISO:MGI.
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:1901216; P:positive regulation of neuron death; IMP:ParkinsonsUK-UCL.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IEA:Ensembl.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0097300; P:programmed necrotic cell death; IMP:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0010941; P:regulation of 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 GO; GO:0042060; P:wound healing; IEA:Ensembl.
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 Pfam; PF19039; ASK_PH; 1.
DR Pfam; PF13281; MAP3K_TRAF_bd; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47769; SSF47769; 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 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
