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Protein

Mitogen-activated protein kinase kinase kinase 5

Gene

Map3k5

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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).5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

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.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei716ATPPROSITE-ProRule annotation1
Active sitei810Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi693 – 701ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • activation of MAPK activity Source: MGI
  • activation of MAPKK activity Source: MGI
  • cellular response to hydrogen peroxide Source: MGI
  • cellular response to reactive nitrogen species Source: MGI
  • cellular response to tumor necrosis factor Source: Ensembl
  • endothelial cell apoptotic process Source: Ensembl
  • innate immune response Source: UniProtKB-KW
  • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • intrinsic apoptotic signaling pathway in response to oxidative stress Source: MGI
  • JNK cascade Source: MGI
  • MAPK cascade Source: UniProtKB
  • p38MAPK cascade Source: CACAO
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of cardiac muscle cell apoptotic process Source: Ensembl
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • positive regulation of JNK cascade Source: ParkinsonsUK-UCL
  • positive regulation of JUN kinase activity Source: MGI
  • positive regulation of myoblast differentiation Source: CACAO
  • positive regulation of neuron death Source: ParkinsonsUK-UCL
  • positive regulation of p38MAPK cascade Source: Ensembl
  • positive regulation of vascular smooth muscle cell proliferation Source: Ensembl
  • programmed necrotic cell death Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of cell death Source: MGI
  • response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • response to ischemia Source: Ensembl
  • wound healing Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Immunity, Innate immunity, Stress response

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiR-MMU-2559580. Oxidative Stress Induced Senescence.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Map3k5
Synonyms:Ask1, Mekk5
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1346876. Map3k5.

Subcellular locationi

  • 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

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862501 – 1380Mitogen-activated protein kinase kinase kinase 5Add BLAST1380

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei90Phosphoserine; by PIM1, PKB/AKT1 and PKB/AKT2By similarity1
Modified residuei725PhosphotyrosineBy similarity1
Modified residuei820Phosphothreonine; by autocatalysisBy similarity1
Modified residuei845Phosphothreonine; by autocatalysis, MELK and MAP3K63 Publications1
Modified residuei849Phosphothreonine; by autocatalysis1 Publication1
Modified residuei965PhosphoserineBy similarity1
Modified residuei973Phosphoserine1 Publication1
Modified residuei1036PhosphoserineBy similarity1
Modified residuei1040PhosphoserineBy similarity1

Post-translational modificationi

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.By similarity4 Publications
Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination leading to proteasomal degradation.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO35099.
MaxQBiO35099.
PaxDbiO35099.
PRIDEiO35099.

PTM databases

iPTMnetiO35099.
PhosphoSitePlusiO35099.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSMUSG00000071369.
CleanExiMM_MAP3K5.
ExpressionAtlasiO35099. baseline and differential.
GenevisibleiO35099. MM.

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Ppp3r1Q638103EBI-777493,EBI-6666164

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • protein phosphatase binding Source: MGI

Protein-protein interaction databases

BioGridi204961. 7 interactors.
DIPiDIP-38055N.
IntActiO35099. 6 interactors.
MINTiMINT-151480.
STRINGi10090.ENSMUSP00000093485.

Structurei

3D structure databases

ProteinModelPortaliO35099.
SMRiO35099.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini687 – 945Protein kinasePROSITE-ProRule annotationAdd BLAST259

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili1252 – 1292Sequence analysisAdd BLAST41

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG4279. Eukaryota.
ENOG410XQGS. LUCA.
GeneTreeiENSGT00800000124036.
HOGENOMiHOG000293286.
HOVERGENiHBG006305.
InParanoidiO35099.
KOiK04426.
OMAiTELHCKK.
OrthoDBiEOG091G00SJ.
TreeFamiTF105115.

Family and domain databases

InterProiIPR025136. DUF4071.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR013761. SAM/pointed.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF13281. DUF4071. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47769. SSF47769. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O35099-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGTEAGEGIT FSVPPFASVG FCTIPEGGSC RRGGGAATAA EGEPSLQPLL
60 70 80 90 100
VPPPPPPPGS FWNVESAAAP GTSCPTTAPG SSATRGRGNS GSGGGRRTTV
110 120 130 140 150
AYVINEASQG QLVVAESEAL QSLREACEAV GATLETLHFG KLDFGETAVL
160 170 180 190 200
DRFYNADIAV VEMSDAFRQP SLFYHLGVRE SFSMANNIIL YCDTNSDSLQ
210 220 230 240 250
SLKEIICQKN TVCTGNYTFI PYMVTPHNKV YCCDSSFMKG LTELMQPNFE
260 270 280 290 300
LLLGPICLPL VDRFVQLLKV AQASSSQYFR ESILSDIRKA RNLYTGKELA
310 320 330 340 350
AELARIRQRV DNIEVLTADI VINLLLSYRD IQDYDSIVKL VETLEKLPTF
360 370 380 390 400
DLASHHHVKF HYAFALNRRN LPGDRAKALD IMIPMVQSEE QVASDMYCLV
410 420 430 440 450
GRIYKDMFLD SNFTDTESRD HGASWFKKAF ESEPTLQSGI NYAVLLLAAG
460 470 480 490 500
HQFESSFELR KVGVKLSSLL GKKGNLEKLQ SYWEVGFFLG ASVLANDHLR
510 520 530 540 550
VIQASEKLFR LKTPAWYLKS IVETILIYKH FVKLTTEQPS AKQELVDFWM
560 570 580 590 600
DFLVEATKTD VTVVRFPVLI LEPTKIYQPS YLSINNEVEE KTISIWHVLP
610 620 630 640 650
DDKKGIHEWN FGASSVRGVS ISKFEERCCF LYVLHNSDDF QIYFCTELHC
660 670 680 690 700
KRFFEMVNTI TEEKGRGAED GDCEGDSLEY DYEYDENGDR VVLGKGTYGI
710 720 730 740 750
VYAGRDLSNQ VRIAIKEIPE RDSRYSQPLH EEIALHKHLK HKNIVQYLGS
760 770 780 790 800
FSENGFIKIF MEQVPGGSLS ALLRSKWGPL KDNEQTIGFY TKQILEGLKY
810 820 830 840 850
LHDNQIVHRD IKGDNVLINT YSGVLKISDF GTSKRLAGIN PCTETFTGTL
860 870 880 890 900
QYMAPEIIDK GPRGYGKAAD IWSLGCTIIE MATGKPPFYE LGEPQAAMFK
910 920 930 940 950
VGMFKVHPEI PESMSAEAKA FILKCFEPDP DKRACANDLL IDEFLKVSSK
960 970 980 990 1000
KKKTQPKLSA LSTGSNEYLR SISLPVPVLV EDTSSSSEYG SVSPDTELKA
1010 1020 1030 1040 1050
DPFSFKARAK SCGEKDGKGI RTLFLGIPDE NFEDHSAPPS PEEKDSGFFM
1060 1070 1080 1090 1100
LRKDSERRAT LHRILTEDQD KVVRNLMESL AQGAEEPKLK WEHITTLISS
1110 1120 1130 1140 1150
LREFVRSTDR KIIATTLSKL KLELDFDSHG ISQVQVVLFG FQDAVNKVLR
1160 1170 1180 1190 1200
NHNIKPHWMF ALDSIIRKAV QTAITILVPE LRPHFSLASE SDTADPEDLD
1210 1220 1230 1240 1250
VEDEHEELSS NQTVRRPQAI TEDAVATSGV STLSSTVSHD SQNAHRSLNV
1260 1270 1280 1290 1300
QLGRMKIETN RLLEELVRKE RELQALLHQA IEEKDQEIRH LKLKSQPIDI
1310 1320 1330 1340 1350
PGFPVCHLNS PGTTTEDSEL PGWLRENGAD EDTISRFLAE DYTLVDVLYY
1360 1370 1380
VTRDDLKCLR LRGGMLCTLW KAIIDFRNKC
Length:1,380
Mass (Da):154,512
Last modified:July 27, 2011 - v3
Checksum:iBE68D225EBBCDF38
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti166A → T in BAA23648 (PubMed:9367868).Curated1
Sequence conflicti368 – 370RRN → TRT in BAA23648 (PubMed:9367868).Curated3
Sequence conflicti1090K → N in BAA23648 (PubMed:9367868).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB006787 mRNA. Translation: BAA23648.3.
BC116627 mRNA. Translation: AAI16628.1.
BC133697 mRNA. Translation: AAI33698.1.
CCDSiCCDS35857.1.
PIRiJC5778.
RefSeqiNP_032606.4. NM_008580.4.
UniGeneiMm.6595.

Genome annotation databases

EnsembliENSMUST00000095806; ENSMUSP00000093485; ENSMUSG00000071369.
GeneIDi26408.
KEGGimmu:26408.
UCSCiuc007enm.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB006787 mRNA. Translation: BAA23648.3.
BC116627 mRNA. Translation: AAI16628.1.
BC133697 mRNA. Translation: AAI33698.1.
CCDSiCCDS35857.1.
PIRiJC5778.
RefSeqiNP_032606.4. NM_008580.4.
UniGeneiMm.6595.

3D structure databases

ProteinModelPortaliO35099.
SMRiO35099.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204961. 7 interactors.
DIPiDIP-38055N.
IntActiO35099. 6 interactors.
MINTiMINT-151480.
STRINGi10090.ENSMUSP00000093485.

PTM databases

iPTMnetiO35099.
PhosphoSitePlusiO35099.

Proteomic databases

EPDiO35099.
MaxQBiO35099.
PaxDbiO35099.
PRIDEiO35099.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000095806; ENSMUSP00000093485; ENSMUSG00000071369.
GeneIDi26408.
KEGGimmu:26408.
UCSCiuc007enm.2. mouse.

Organism-specific databases

CTDi4217.
MGIiMGI:1346876. Map3k5.

Phylogenomic databases

eggNOGiKOG4279. Eukaryota.
ENOG410XQGS. LUCA.
GeneTreeiENSGT00800000124036.
HOGENOMiHOG000293286.
HOVERGENiHBG006305.
InParanoidiO35099.
KOiK04426.
OMAiTELHCKK.
OrthoDBiEOG091G00SJ.
TreeFamiTF105115.

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiR-MMU-2559580. Oxidative Stress Induced Senescence.

Miscellaneous databases

ChiTaRSiMap3k5. mouse.
PROiO35099.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000071369.
CleanExiMM_MAP3K5.
ExpressionAtlasiO35099. baseline and differential.
GenevisibleiO35099. MM.

Family and domain databases

InterProiIPR025136. DUF4071.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR013761. SAM/pointed.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF13281. DUF4071. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47769. SSF47769. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiM3K5_MOUSE
AccessioniPrimary (citable) accession number: O35099
Secondary accession number(s): Q14AY5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: November 2, 2016
This is version 152 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.