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Q99683 (M3K5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 156. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | 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, MAPKKK5, MEKK5
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1374 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.1 Ref.2 Ref.5 Ref.6 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.17 Ref.18 Ref.20 Ref.22 Ref.23 Ref.28 Ref.32 Ref.45

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

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-838 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylation of Ser-966 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-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Ref.5 Ref.6 Ref.8 Ref.10 Ref.12 Ref.14 Ref.17 Ref.18 Ref.19 Ref.20 Ref.23 Ref.25 Ref.29 Ref.31

Subunit structure

Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Associates with and inhibited by HIV-1 Nef. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis. Interacts with SOCS1 which recognizes phosphorylation of Tyr-718 and induces MAP3K5/ASK1 degradation in endothelial cells. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN. Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PGAM5, PIM1, PPP5C, SOCS1, STUB1, TRAF2, TRAF6 and TXN. Interacts with ERN1 in a TRAF2-dependent manner. Interacts with calcineurin subunit PPP3R1 and with PPM1L By similarity. 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. Interacts with DUSP13/DUSP13A; may positively regulate apoptosis. Ref.5 Ref.6 Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21 Ref.22 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.32 Ref.33 Ref.34 Ref.35 Ref.40 Ref.41 Ref.44

Subcellular location

Cytoplasm. Endoplasmic reticulum. Note: Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region. Ref.12 Ref.19 Ref.22 Ref.27

Tissue specificity

Abundantly expressed in heart and pancreas.

Induction

By TNF. Inhibited by HIV-1 Nef. Ref.5 Ref.6 Ref.8 Ref.10 Ref.12 Ref.14 Ref.17 Ref.18 Ref.19 Ref.20 Ref.23 Ref.25 Ref.29 Ref.31

Post-translational modification

Phosphorylated at Thr-838 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylated at Ser-966 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5. Ref.12 Ref.14 Ref.18 Ref.19 Ref.20 Ref.23 Ref.25 Ref.29 Ref.31 Ref.36 Ref.40 Ref.41 Ref.45 Ref.46

Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination leading to proteasomal degradation. Ref.26 Ref.32

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
Host-virus interaction
Immunity
Innate immunity
Stress response
   Cellular componentCytoplasm
Endoplasmic reticulum
   Coding sequence diversityPolymorphism
   DomainCoiled coil
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Inferred from direct assay PubMed 21771788. Source: UniProtKB

MAPK cascade

Inferred from direct assay Ref.31PubMed 21771788. Source: UniProtKB

activation of JUN kinase activity

Traceable author statement Ref.2. Source: ProtInc

activation of MAPKK activity

Inferred from direct assay PubMed 11959862. Source: BHF-UCL

activation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 14761963. Source: GOC

apoptotic signaling pathway

Traceable author statement Ref.2. Source: ProtInc

cellular response to hydrogen peroxide

Inferred from direct assay PubMed 20674765. Source: BHF-UCL

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

intrinsic apoptotic signaling pathway in response to oxidative stress

Inferred from direct assay PubMed 21771788. Source: UniProtKB

positive regulation of apoptotic process

Inferred from direct assay PubMed 21771788. Source: UniProtKB

positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 20674765. Source: BHF-UCL

positive regulation of neuron death

Inferred from genetic interaction PubMed 15983381. Source: ParkinsonsUK-UCL

protein phosphorylation

Inferred from direct assay PubMed 15983381. Source: ParkinsonsUK-UCL

response to ischemia

Inferred from electronic annotation. Source: Ensembl

viral process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

endoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

protein kinase complex

Inferred from direct assay PubMed 15983381. Source: ParkinsonsUK-UCL

   Molecular_functionATP binding

Inferred from direct assay Ref.31. Source: UniProtKB

MAP kinase kinase kinase activity

Inferred from direct assay Ref.31. Source: UniProtKB

cysteine-type endopeptidase activator activity involved in apoptotic process

Inferred from direct assay PubMed 14761963. Source: UniProtKB

magnesium ion binding

Inferred from direct assay Ref.31. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.15Ref.19PubMed 14761963Ref.33. Source: UniProtKB

protein homodimerization activity

Inferred from direct assay Ref.18. Source: UniProtKB

protein kinase activity

Inferred from direct assay PubMed 21771788. Source: UniProtKB

protein phosphatase binding

Inferred from physical interaction PubMed 11959862PubMed 20674765. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 13741374Mitogen-activated protein kinase kinase kinase 5
PRO_0000086249

Regions

Domain680 – 938259Protein kinase
Nucleotide binding686 – 6949ATP By similarity
Coiled coil1245 – 128541 Potential

Sites

Active site8031Proton acceptor By similarity
Binding site7091ATP

Amino acid modifications

Modified residue831Phosphoserine; by PIM1, PKB/AKT1 and PKB/AKT2 Ref.14 Ref.20 Ref.40
Modified residue7181Phosphotyrosine Ref.29
Modified residue8131Phosphothreonine; by autocatalysis Ref.46
Modified residue8381Phosphothreonine; by autocatalysis, MELK and MAP3K6 Ref.12 Ref.18 Ref.31 Ref.36 Ref.41 Ref.45 Ref.46
Modified residue8421Phosphothreonine; by autocatalysis Ref.46
Modified residue9581Phosphoserine
Modified residue9661Phosphoserine Ref.23 Ref.25 Ref.41
Modified residue9761Phosphothreonine By similarity
Modified residue10291Phosphoserine Ref.37 Ref.38
Modified residue10331Phosphoserine Ref.25 Ref.37 Ref.38 Ref.39 Ref.41

Natural variations

Natural variant10061G → R. Ref.47
Corresponds to variant rs45626535 [ dbSNP | Ensembl ].
VAR_040693
Natural variant12141I → T. Ref.47
Corresponds to variant rs56379668 [ dbSNP | Ensembl ].
VAR_040694
Natural variant12501I → V. Ref.47
Corresponds to variant rs35551087 [ dbSNP | Ensembl ].
VAR_040695
Natural variant13141T → I. Ref.47
Corresponds to variant rs45599539 [ dbSNP | Ensembl ].
VAR_040696
Natural variant13151D → N. Ref.47
Corresponds to variant rs41288957 [ dbSNP | Ensembl ].
VAR_040697

Experimental info

Mutagenesis7091K → M: Loss of kinase activity. Inhibits activation of JNK and apoptosis mediated by TNFRSF6 and DAXX. Ref.7 Ref.31
Mutagenesis7091K → R: Loss of kinase activity. Abolishes DAXX-mediated apoptosis. Ref.7 Ref.31
Mutagenesis9661S → A: Enhanced induction of apoptosis, increased kinase activity, and loss of YWHAG binding. Ref.8 Ref.25
Mutagenesis10331S → A: Enhanced induction of apoptosis and increased kinase activity. Ref.25

Secondary structure

.................................................... 1374
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99683 [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: 265BDC65968AF985

FASTA1,374154,537
        10         20         30         40         50         60 
MSTEADEGIT FSVPPFAPSG FCTIPEGGIC RRGGAAAVGE GEEHQLPPPP PGSFWNVESA 

        70         80         90        100        110        120 
AAPGIGCPAA TSSSSATRGR GSSVGGGSRR TTVAYVINEA SQGQLVVAES EALQSLREAC 

       130        140        150        160        170        180 
ETVGATLETL HFGKLDFGET TVLDRFYNAD IAVVEMSDAF RQPSLFYHLG VRESFSMANN 

       190        200        210        220        230        240 
IILYCDTNSD SLQSLKEIIC QKNTMCTGNY TFVPYMITPH NKVYCCDSSF MKGLTELMQP 

       250        260        270        280        290        300 
NFELLLGPIC LPLVDRFIQL LKVAQASSSQ YFRESILNDI RKARNLYTGK ELAAELARIR 

       310        320        330        340        350        360 
QRVDNIEVLT ADIVINLLLS YRDIQDYDSI VKLVETLEKL PTFDLASHHH VKFHYAFALN 

       370        380        390        400        410        420 
RRNLPGDRAK ALDIMIPMVQ SEGQVASDMY CLVGRIYKDM FLDSNFTDTE SRDHGASWFK 

       430        440        450        460        470        480 
KAFESEPTLQ SGINYAVLLL AAGHQFESSF ELRKVGVKLS SLLGKKGNLE KLQSYWEVGF 

       490        500        510        520        530        540 
FLGASVLAND HMRVIQASEK LFKLKTPAWY LKSIVETILI YKHFVKLTTE QPVAKQELVD 

       550        560        570        580        590        600 
FWMDFLVEAT KTDVTVVRFP VLILEPTKIY QPSYLSINNE VEEKTISIWH VLPDDKKGIH 

       610        620        630        640        650        660 
EWNFSASSVR GVSISKFEER CCFLYVLHNS DDFQIYFCTE LHCKKFFEMV NTITEEKGRS 

       670        680        690        700        710        720 
TEEGDCESDL LEYDYEYDEN GDRVVLGKGT YGIVYAGRDL SNQVRIAIKE IPERDSRYSQ 

       730        740        750        760        770        780 
PLHEEIALHK HLKHKNIVQY LGSFSENGFI KIFMEQVPGG SLSALLRSKW GPLKDNEQTI 

       790        800        810        820        830        840 
GFYTKQILEG LKYLHDNQIV HRDIKGDNVL INTYSGVLKI SDFGTSKRLA GINPCTETFT 

       850        860        870        880        890        900 
GTLQYMAPEI IDKGPRGYGK AADIWSLGCT IIEMATGKPP FYELGEPQAA MFKVGMFKVH 

       910        920        930        940        950        960 
PEIPESMSAE AKAFILKCFE PDPDKRACAN DLLVDEFLKV SSKKKKTQPK LSALSAGSNE 

       970        980        990       1000       1010       1020 
YLRSISLPVP VLVEDTSSSS EYGSVSPDTE LKVDPFSFKT RAKSCGERDV KGIRTLFLGI 

      1030       1040       1050       1060       1070       1080 
PDENFEDHSA PPSPEEKDSG FFMLRKDSER RATLHRILTE DQDKIVRNLM ESLAQGAEEP 

      1090       1100       1110       1120       1130       1140 
KLKWEHITTL IASLREFVRS TDRKIIATTL SKLKLELDFD SHGISQVQVV LFGFQDAVNK 

      1150       1160       1170       1180       1190       1200 
VLRNHNIKPH WMFALDSIIR KAVQTAITIL VPELRPHFSL ASESDTADQE DLDVEDDHEE 

      1210       1220       1230       1240       1250       1260 
QPSNQTVRRP QAVIEDAVAT SGVSTLSSTV SHDSQSAHRS LNVQLGRMKI ETNRLLEELV 

      1270       1280       1290       1300       1310       1320 
RKEKELQALL HRAIEEKDQE IKHLKLKSQP IEIPELPVFH LNSSGTNTED SELTDWLRVN 

      1330       1340       1350       1360       1370 
GADEDTISRF LAEDYTLLDV LYYVTRDDLK CLRLRGGMLC TLWKAIIDFR NKQT 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase."
Wang X.S., Diener K., Jannuzzi D., Trollinger D., Tan T.-H., Lichenstein H., Zukowski M., Yao Z.
J. Biol. Chem. 271:31607-31611(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]"Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways."
Ichijo H., Nishida E., Irie K., ten Dijke P., Saitoh M., Moriguchi T., Takagi M., Matsumoto K., Miyazono K., Gotoh Y.
Science 275:90-94(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[3]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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].
Tissue: Eye and Lung.
[5]"Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1."
Saitoh M., Nishitoh H., Fujii M., Takeda K., Tobiume K., Sawada Y., Kawabata M., Miyazono K., Ichijo H.
EMBO J. 17:2596-2606(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TXN, ENZYME REGULATION, FUNCTION.
[6]"ASK1 is essential for JNK/SAPK activation by TRAF2."
Nishitoh H., Saitoh M., Mochida Y., Takeda K., Nakano H., Rothe M., Miyazono K., Ichijo H.
Mol. Cell 2:389-395(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, INTERACTION WITH TRAF2, FUNCTION.
[7]"Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx."
Chang H.Y., Nishitoh H., Yang X., Ichijo H., Baltimore D.
Science 281:1860-1863(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAXX, MUTAGENESIS OF LYS-709.
[8]"Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins."
Zhang L., Chen J., Fu H.
Proc. Natl. Acad. Sci. U.S.A. 96:8511-8515(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH 14-3-3 PROTEINS, ENZYME REGULATION, MUTAGENESIS OF SER-966, FUNCTION.
[9]"Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation."
Hatai T., Matsuzawa A., Inoshita S., Mochida Y., Kuroda T., Sakamaki K., Kuida K., Yonehara S., Ichijo H., Takeda K.
J. Biol. Chem. 275:26576-26581(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN APOPTOSIS.
[10]"Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin."
Liu H., Nishitoh H., Ichijo H., Kyriakis J.M.
Mol. Cell. Biol. 20:2198-2208(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, INTERACTION WITH TRAF2, ENZYME REGULATION, FUNCTION.
[11]"Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3."
McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T., Davis R.J., Lefkowitz R.J.
Science 290:1574-1577(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
[12]"Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress."
Morita K., Saitoh M., Tobiume K., Matsuura H., Enomoto S., Nishitoh H., Ichijo H.
EMBO J. 20:6028-6036(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP5C, DEPHOSPHORYLATION AT THR-838, SUBCELLULAR LOCATION, ENZYME REGULATION, FUNCTION.
[13]"Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation."
Sayama K., Hanakawa Y., Shirakata Y., Yamasaki K., Sawada Y., Sun L., Yamanishi K., Ichijo H., Hashimoto K.
J. Biol. Chem. 276:999-1004(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN KERATINOCYTE DIFFERENTIATION.
[14]"Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1."
Kim A.H., Khursigara G., Sun X., Franke T.F., Chao M.V.
Mol. Cell. Biol. 21:893-901(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-83, ENZYME REGULATION, FUNCTION.
[15]"HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell."
Geleziunas R., Xu W., Takeda K., Ichijo H., Greene W.C.
Nature 410:834-838(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIV-1 NEF, INHIBITION BY HIV-1 NEF.
[16]"Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism."
Chen J., Fujii K., Zhang L., Roberts T., Fu H.
Proc. Natl. Acad. Sci. U.S.A. 98:7783-7788(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RAF1.
[17]"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: INTERACTION WITH TRAF2 AND ERN1, ENZYME REGULATION, FUNCTION IN ER STRESS RESPONSE.
[18]"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: FUNCTION, HOMODIMERIZATION, ENZYME REGULATION, PHOSPHORYLATION AT THR-838.
[19]"Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1)."
Galvan V., Logvinova A., Sperandio S., Ichijo H., Bredesen D.E.
J. Biol. Chem. 278:13325-13332(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IGF1R, PHOSPHORYLATION, ENZYME REGULATION, SUBCELLULAR LOCATION.
[20]"AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance."
Yuan Z.Q., Feldman R.I., Sussman G.E., Coppola D., Nicosia S.V., Cheng J.Q.
J. Biol. Chem. 278:23432-23440(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-83, ENZYME REGULATION, FUNCTION.
[21]"AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3."
Zhang R., He X., Liu W., Lu M., Hsieh J.-T., Min W.
J. Clin. Invest. 111:1933-1943(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2IP.
[22]"Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3 proteins."
Subramanian R.R., Zhang H., Wang H., Ichijo H., Miyashita T., Fu H.
Exp. Cell Res. 294:581-591(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH YWHAB; YWHAE; YWHAH; YWHAQ; YWHAZ AND SFN, FUNCTION, SUBCELLULAR LOCATION.
[23]"Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation."
Goldman E.H., Chen L., Fu H.
J. Biol. Chem. 279:10442-10449(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-966, ENZYME REGULATION, FUNCTION.
[24]"AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation."
Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.
J. Biol. Chem. 279:44955-44965(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2IP.
[25]"Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034."
Fujii K., Goldman E.H., Park H.R., Zhang L., Chen J., Fu H.
Oncogene 23:5099-5104(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-966 AND SER-1033, MUTAGENESIS OF SER-966 AND SER-1033, INTERACTION WITH YWHAG.
[26]"C-terminus of heat shock protein 70-interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1-dependent apoptosis."
Hwang J.R., Zhang C., Patterson C.
Cell Stress Chaperones 10:147-156(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH STUB1, UBIQUITINATION.
[27]"Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation."
Li X., Zhang R., Luo D., Park S.-J., Wang Q., Kim Y., Min W.
J. Biol. Chem. 280:15061-15070(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIPK1, SUBCELLULAR LOCATION.
[28]"Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death."
Noguchi T., Takeda K., Matsuzawa A., Saegusa K., Nakano H., Gohda J., Inoue J., Ichijo H.
J. Biol. Chem. 280:37033-37040(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, INTERACTION WITH TRAF2, FUNCTION.
[29]"SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation."
He Y., Zhang W., Zhang R., Zhang H., Min W.
J. Biol. Chem. 281:5559-5566(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-718, INTERACTION WITH SOCS1, ENZYME REGULATION.
[30]"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.
[31]"Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1."
Takeda K., Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I., Tobiume K., Saitoh M., Matsuzawa A., Ichijo H.
J. Biol. Chem. 282:7522-7531(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, INTERACTION WITH MAP3K5, PHOSPHORYLATION AT THR-838, MUTAGENESIS OF LYS-709.
[32]"Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling."
Zhao Y., Conze D.B., Hanover J.A., Ashwell J.D.
J. Biol. Chem. 282:7777-7782(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BIRC2, UBIQUITINATION, FUNCTION.
[33]"RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation."
Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.
J. Biol. Chem. 282:14788-14796(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2IP.
[34]"Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1."
Fujino G., Noguchi T., Matsuzawa A., Yamauchi S., Saitoh M., Takeda K., Ichijo H.
Mol. Cell. Biol. 27:8152-8163(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRAF2; TRAF6 AND TXN.
[35]"The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3 activation by binding to its nonconserved N terminus."
Guo C., Whitmarsh A.J.
J. Biol. Chem. 283:15903-15911(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
[36]"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-838.
[37]"Phosphoproteome of resting human platelets."
Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A.
J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1029 AND SER-1033, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Platelet.
[38]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1029 AND SER-1033, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[39]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1033, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[40]"PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis."
Gu J.J., Wang Z., Reeves R., Magnuson N.S.
Oncogene 28:4261-4271(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-83 BY PIM1, INTERACTION WITH PIM1.
[41]"Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1."
Takeda K., Komuro Y., Hayakawa T., Oguchi H., Ishida Y., Murakami S., Noguchi T., Kinoshita H., Sekine Y., Iemura S., Natsume T., Ichijo H.
Proc. Natl. Acad. Sci. U.S.A. 106:12301-12305(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PGAM5, PHOSPHORYLATION AT THR-838; SER-966 AND SER-1033.
[42]"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.
[43]"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.
[44]"Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A."
Park J.E., Park B.C., Kim H.A., Song M., Park S.G., Lee D.H., Kim H.J., Choi H.K., Kim J.T., Cho S.
Cell. Mol. Life Sci. 67:2619-2629(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DUSP13.
[45]"The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5."
Sekine Y., Hatanaka R., Watanabe T., Sono N., Iemura S., Natsume T., Kuranaga E., Miura M., Takeda K., Ichijo H.
Mol. Cell 48:692-704(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-838, DEPHOSPHORYLATION AT THR-838 BY PPP5C.
[46]"Structural and functional characterization of the human protein kinase ASK1."
Bunkoczi G., Salah E., Filippakopoulos P., Fedorov O., Muller S., Sobott F., Parker S.A., Zhang H., Min W., Turk B.E., Knapp S.
Structure 15:1215-1226(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 659-951, PHOSPHORYLATION AT THR-813; THR-838 AND THR-842.
[47]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-1006; THR-1214; VAL-1250; ILE-1314 AND ASN-1315.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U67156 mRNA. Translation: AAC50894.1.
D84476 mRNA. Translation: BAA12684.2.
AL024508, AL121933 Genomic DNA. Translation: CAI20176.1.
AL121933, AL024508 Genomic DNA. Translation: CAI15470.1.
BC054503 mRNA. Translation: AAH54503.1.
BC088829 mRNA. Translation: AAH88829.1.
CCDSCCDS5179.1.
RefSeqNP_005914.1. NM_005923.3.
UniGeneHs.186486.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2CLQX-ray2.30A/B659-951[»]
3VW6X-ray2.40A/B671-939[»]
4BF2X-ray2.11A/B660-977[»]
4BHNX-ray2.30A/B660-977[»]
4BIBX-ray2.43A/B660-977[»]
4BICX-ray2.62A/B660-977[»]
4BIDX-ray2.80A/B660-977[»]
4BIEX-ray2.36A/B660-977[»]
ProteinModelPortalQ99683.
SMRQ99683. Positions 650-962.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110381. 74 interactions.
DIPDIP-29516N.
IntActQ99683. 38 interactions.
MINTMINT-99796.
STRING9606.ENSP00000351908.

Chemistry

BindingDBQ99683.
ChEMBLCHEMBL5285.
GuidetoPHARMACOLOGY2080.

PTM databases

PhosphoSiteQ99683.

Polymorphism databases

DMDM6685617.

Proteomic databases

MaxQBQ99683.
PaxDbQ99683.
PRIDEQ99683.

Protocols and materials databases

DNASU4217.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000359015; ENSP00000351908; ENSG00000197442.
GeneID4217.
KEGGhsa:4217.
UCSCuc003qhc.3. human.

Organism-specific databases

CTD4217.
GeneCardsGC06M136919.
HGNCHGNC:6857. MAP3K5.
HPACAB007824.
MIM602448. gene.
neXtProtNX_Q99683.
PharmGKBPA30601.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG006305.
InParanoidQ99683.
KOK04426.
OMATELHCKK.
OrthoDBEOG7WDN1P.
PhylomeDBQ99683.
TreeFamTF105115.

Enzyme and pathway databases

BRENDA2.7.12.2. 2681.
ReactomeREACT_120956. Cellular responses to stress.
SignaLinkQ99683.

Gene expression databases

ArrayExpressQ99683.
BgeeQ99683.
CleanExHS_MAP3K5.
GenevestigatorQ99683.

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

ChiTaRSMAP3K5. human.
EvolutionaryTraceQ99683.
GeneWikiASK1.
GenomeRNAi4217.
NextBio16633.
PROQ99683.
SOURCESearch...

Entry information

Entry nameM3K5_HUMAN
AccessionPrimary (citable) accession number: Q99683
Secondary accession number(s): Q5THN3, Q99461
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: May 1, 1997
Last modified: July 9, 2014
This is version 156 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM