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O35099 (M3K5_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 5

EC=2.7.11.25
Alternative name(s):
Apoptosis signal-regulating kinase 1
Short name=ASK-1
MAPK/ERK kinase kinase 5
Short name=MEK kinase 5
Short name=MEKK 5
Gene names
Name:Map3k5
Synonyms:Ask1, Mekk5
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1380 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). Ref.4 Ref.6 Ref.7 Ref.8 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Activated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C-terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase. Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-845 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylation of Ser-973 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site. SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Ref.5 Ref.7 Ref.9

Subunit structure

Homodimer when inactive By similarity. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF By similarity. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis By similarity. Interacts with SOCS1 which recognizes phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells By similarity. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN By similarity. Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PIM1, PGAM5, PPP5C, SOCS1, STUB1, TRAF2 and TXN By similarity. Interacts with ERN1 in a TRAF2-dependent manner By similarity. Interacts with calcineurin subunit PPP3R1, PPM1L and TRAF6. Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5. Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner By similarity.Interacts with DUSP13/DUSP13A; may positively regulate apoptosis By similarity. Ref.7 Ref.9 Ref.10 Ref.14

Subcellular location

Cytoplasm By similarity. Endoplasmic reticulum By similarity. Note: Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region By similarity.

Tissue specificity

Expressed in various adult mouse tissues including heart, brain, lung, liver and kidney. Ref.1

Post-translational modification

Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2 By similarity. Phosphorylated at Ser-973 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity By similarity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5 By similarity. Phosphorylated at Thr-845 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-845 is dephosphorylated by PPP5C. Ref.5 Ref.9 Ref.11 Ref.14

Ubiquitinated By similarity. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination leading to proteasomal degradation By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Immunity
Innate immunity
Stress response
   Cellular componentCytoplasm
Endoplasmic reticulum
   DomainCoiled coil
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Inferred from electronic annotation. Source: Ensembl

MAPK cascade

Inferred from sequence or structural similarity. Source: UniProtKB

activation of MAPK activity

Inferred from direct assay PubMed 15767678. Source: MGI

cellular response to hydrogen peroxide

Inferred from electronic annotation. Source: Ensembl

cellular response to reactive nitrogen species

Inferred from mutant phenotype PubMed 18007661. Source: MGI

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

intrinsic apoptotic signaling pathway in response to oxidative stress

Inferred from direct assay Ref.11. Source: MGI

positive regulation of apoptotic process

Inferred from direct assay Ref.11. Source: UniProtKB

programmed necrotic cell death

Inferred from mutant phenotype PubMed 18007661. Source: MGI

regulation of cell death

Inferred from genetic interaction PubMed 19451227. Source: MGI

response to ischemia

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentendoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from sequence or structural similarity. Source: UniProtKB

MAP kinase kinase kinase activity

Inferred from direct assay Ref.11. Source: UniProtKB

cysteine-type endopeptidase activator activity involved in apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

magnesium ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein homodimerization activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein kinase binding

Inferred from physical interaction Ref.11. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Ppp3r1Q638103EBI-777493,EBI-6666164

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 13801380Mitogen-activated protein kinase kinase kinase 5
PRO_0000086250

Regions

Domain687 – 945259Protein kinase
Nucleotide binding693 – 7019ATP By similarity
Coiled coil1252 – 129241 Potential

Sites

Active site8101Proton acceptor By similarity
Binding site7161ATP By similarity

Amino acid modifications

Modified residue901Phosphoserine; by PIM1, PKB/AKT1 and PKB/AKT2 By similarity
Modified residue7251Phosphotyrosine By similarity
Modified residue8201Phosphothreonine; by autocatalysis By similarity
Modified residue8451Phosphothreonine; by autocatalysis, MELK and MAP3K6 Ref.5 Ref.11 Ref.14
Modified residue8491Phosphothreonine; by autocatalysis Ref.5
Modified residue9651Phosphoserine By similarity
Modified residue9731Phosphoserine By similarity
Modified residue9831Phosphothreonine
Modified residue10361Phosphoserine By similarity
Modified residue10401Phosphoserine By similarity

Experimental info

Sequence conflict1661A → T in BAA23648. Ref.1
Sequence conflict368 – 3703RRN → TRT in BAA23648. Ref.1
Sequence conflict10901K → N in BAA23648. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O35099 [UniParc].

Last modified July 27, 2011. Version 3.
Checksum: BE68D225EBBCDF38

FASTA1,380154,512
        10         20         30         40         50         60 
MGTEAGEGIT FSVPPFASVG FCTIPEGGSC RRGGGAATAA EGEPSLQPLL VPPPPPPPGS 

        70         80         90        100        110        120 
FWNVESAAAP GTSCPTTAPG SSATRGRGNS GSGGGRRTTV AYVINEASQG QLVVAESEAL 

       130        140        150        160        170        180 
QSLREACEAV GATLETLHFG KLDFGETAVL DRFYNADIAV VEMSDAFRQP SLFYHLGVRE 

       190        200        210        220        230        240 
SFSMANNIIL YCDTNSDSLQ SLKEIICQKN TVCTGNYTFI PYMVTPHNKV YCCDSSFMKG 

       250        260        270        280        290        300 
LTELMQPNFE LLLGPICLPL VDRFVQLLKV AQASSSQYFR ESILSDIRKA RNLYTGKELA 

       310        320        330        340        350        360 
AELARIRQRV DNIEVLTADI VINLLLSYRD IQDYDSIVKL VETLEKLPTF DLASHHHVKF 

       370        380        390        400        410        420 
HYAFALNRRN LPGDRAKALD IMIPMVQSEE QVASDMYCLV GRIYKDMFLD SNFTDTESRD 

       430        440        450        460        470        480 
HGASWFKKAF ESEPTLQSGI NYAVLLLAAG HQFESSFELR KVGVKLSSLL GKKGNLEKLQ 

       490        500        510        520        530        540 
SYWEVGFFLG ASVLANDHLR VIQASEKLFR LKTPAWYLKS IVETILIYKH FVKLTTEQPS 

       550        560        570        580        590        600 
AKQELVDFWM DFLVEATKTD VTVVRFPVLI LEPTKIYQPS YLSINNEVEE KTISIWHVLP 

       610        620        630        640        650        660 
DDKKGIHEWN FGASSVRGVS ISKFEERCCF LYVLHNSDDF QIYFCTELHC KRFFEMVNTI 

       670        680        690        700        710        720 
TEEKGRGAED GDCEGDSLEY DYEYDENGDR VVLGKGTYGI VYAGRDLSNQ VRIAIKEIPE 

       730        740        750        760        770        780 
RDSRYSQPLH EEIALHKHLK HKNIVQYLGS FSENGFIKIF MEQVPGGSLS ALLRSKWGPL 

       790        800        810        820        830        840 
KDNEQTIGFY TKQILEGLKY LHDNQIVHRD IKGDNVLINT YSGVLKISDF GTSKRLAGIN 

       850        860        870        880        890        900 
PCTETFTGTL QYMAPEIIDK GPRGYGKAAD IWSLGCTIIE MATGKPPFYE LGEPQAAMFK 

       910        920        930        940        950        960 
VGMFKVHPEI PESMSAEAKA FILKCFEPDP DKRACANDLL IDEFLKVSSK KKKTQPKLSA 

       970        980        990       1000       1010       1020 
LSTGSNEYLR SISLPVPVLV EDTSSSSEYG SVSPDTELKA DPFSFKARAK SCGEKDGKGI 

      1030       1040       1050       1060       1070       1080 
RTLFLGIPDE NFEDHSAPPS PEEKDSGFFM LRKDSERRAT LHRILTEDQD KVVRNLMESL 

      1090       1100       1110       1120       1130       1140 
AQGAEEPKLK WEHITTLISS LREFVRSTDR KIIATTLSKL KLELDFDSHG ISQVQVVLFG 

      1150       1160       1170       1180       1190       1200 
FQDAVNKVLR NHNIKPHWMF ALDSIIRKAV QTAITILVPE LRPHFSLASE SDTADPEDLD 

      1210       1220       1230       1240       1250       1260 
VEDEHEELSS NQTVRRPQAI TEDAVATSGV STLSSTVSHD SQNAHRSLNV QLGRMKIETN 

      1270       1280       1290       1300       1310       1320 
RLLEELVRKE RELQALLHQA IEEKDQEIRH LKLKSQPIDI PGFPVCHLNS PGTTTEDSEL 

      1330       1340       1350       1360       1370       1380 
PGWLRENGAD EDTISRFLAE DYTLVDVLYY VTRDDLKCLR LRGGMLCTLW KAIIDFRNKC 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and characterization of the mouse apoptosis signal-regulating kinase 1."
Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.
Biochem. Biophys. Res. Commun. 239:905-910(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
[2]Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION TO 22-26; 123; 273; 755; 1001-1011; 1220-1222 AND 1274-1280.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]"ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis."
Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., Minowa O., Miyazono K., Noda T., Ichijo H.
EMBO Rep. 2:222-228(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[5]"Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer."
Tobiume K., Saitoh M., Ichijo H.
J. Cell. Physiol. 191:95-104(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-845 AND THR-849, ENZYME REGULATION.
[6]"Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation."
Takeda K., Matsuzawa A., Nishitoh H., Tobiume K., Kishida S., Ninomiya-Tsuji J., Matsumoto K., Ichijo H.
EMBO Rep. 5:161-166(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity."
Matsuzawa A., Saegusa K., Noguchi T., Sadamitsu C., Nishitoh H., Nagai S., Koyasu S., Matsumoto K., Takeda K., Ichijo H.
Nat. Immunol. 6:587-592(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, INTERACTION WITH TRAF6.
[8]"A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation."
Rubiolo C., Piazzolla D., Meissl K., Beug H., Huber J.C., Kolbus A., Baccarini M.
Blood 108:152-159(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth."
Liu Q., Wilkins B.J., Lee Y.J., Ichijo H., Molkentin J.D.
Mol. Cell. Biol. 26:3785-3797(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP3R1, PHOSPHORYLATION AT SER-973, ENZYME REGULATION, FUNCTION.
[10]"Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase 2Cepsilon."
Saito J., Toriumi S., Awano K., Ichijo H., Sasaki K., Kobayashi T., Tamura S.
Biochem. J. 405:591-596(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPM1L.
[11]"Murine protein serine/threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr 838 phosphorylation."
Jung H., Seong H.A., Ha H.
J. Biol. Chem. 283:34541-34553(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-845.
[12]"Apoptosis signal-regulating kinase 1 in stress and immune response."
Takeda K., Noguchi T., Naguro I., Ichijo H.
Annu. Rev. Pharmacol. Toxicol. 48:199-225(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
[13]"The roles of ASK family proteins in stress responses and diseases."
Hattori K., Naguro I., Runchel C., Ichijo H.
Cell Commun. Signal. 7:9-9(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
[14]"S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation."
Yamaguchi F., Umeda Y., Shimamoto S., Tsuchiya M., Tokumitsu H., Tokuda M., Kobayashi R.
J. Biol. Chem. 287:13787-13798(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP5C, PHOSPHORYLATION AT THR-845, DEPHOSPHORYLATION AT THR-845 BY PPP5C.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB006787 mRNA. Translation: BAA23648.3.
BC116627 mRNA. Translation: AAI16628.1.
BC133697 mRNA. Translation: AAI33698.1.
PIRJC5778.
RefSeqNP_032606.4. NM_008580.4.
UniGeneMm.6595.

3D structure databases

ProteinModelPortalO35099.
SMRO35099. Positions 653-948.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204961. 7 interactions.
IntActO35099. 6 interactions.
MINTMINT-151480.
STRING10090.ENSMUSP00000093485.

PTM databases

PhosphoSiteO35099.

Proteomic databases

PaxDbO35099.
PRIDEO35099.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000095806; ENSMUSP00000093485; ENSMUSG00000071369.
GeneID26408.
KEGGmmu:26408.
UCSCuc007enm.2. mouse.

Organism-specific databases

CTD4217.
MGIMGI:1346876. Map3k5.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117243.
HOGENOMHOG000293286.
HOVERGENHBG006305.
InParanoidQ14AY5.
KOK04426.
OMATELHCKK.
OrthoDBEOG7WDN1P.
TreeFamTF105115.

Enzyme and pathway databases

BRENDA2.7.12.2. 3474.

Gene expression databases

ArrayExpressO35099.
BgeeO35099.
CleanExMM_MAP3K5.
GenevestigatorO35099.

Family and domain databases

InterProIPR025136. DUF4071.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR013761. SAM/pointed.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF13281. DUF4071. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF47769. SSF47769. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304389.
PROO35099.
SOURCESearch...

Entry information

Entry nameM3K5_MOUSE
AccessionPrimary (citable) accession number: O35099
Secondary accession number(s): Q14AY5
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: April 16, 2014
This is version 125 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot