Q99683 (M3K5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	MAP3K5
Synonyms:	ASK1, MAPKKK5, MEKK5

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1374 AA.
Sequence status	Complete.
Protein existence	Evidence 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
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. 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.39 Ref.40
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.35 Ref.39 Ref.40 Ref.43 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 process	Apoptosis Host-virus interaction Immunity Innate immunity Stress response
Cellular component	Cytoplasm Endoplasmic reticulum
Coding sequence diversity	Polymorphism
Domain	Coiled coil
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of JUN kinase activity 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 virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP 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 homodimerization activity Inferred from direct assay Ref.18. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-476263,EBI-476263
AKT1	P31749	2	EBI-476263,EBI-296087
DAXX	Q9UER7	6	EBI-476263,EBI-77321
MAP2K3	P46734	2	EBI-476263,EBI-602462
Map3k6	Q9WTR2	3	EBI-476263,EBI-1254790	From a different organism.
TXN	P10599	2	EBI-476263,EBI-594644
YWHAB	P31946	3	EBI-476263,EBI-359815
YWHAZ	P63104	2	EBI-476263,EBI-347088
ZNF622	Q969S3	14	EBI-476263,EBI-2687480

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1374

1374

Mitogen-activated protein kinase kinase kinase 5

PRO_0000086249

Regions

Domain

680 – 938

259

Protein kinase

Nucleotide binding

686 – 694

9

ATP By similarity

Coiled coil

1245 – 1285

41

Potential

Sites

Active site

803

1

Proton acceptor By similarity

Binding site

709

1

ATP

Amino acid modifications

Modified residue

83

1

Phosphoserine; by PIM1, PKB/AKT1 and PKB/AKT2 Ref.14 Ref.20 Ref.39

Modified residue

718

1

Phosphotyrosine Ref.29

Modified residue

813

1

Phosphothreonine; by autocatalysis Ref.43

Modified residue

838

1

Phosphothreonine; by autocatalysis, MELK and MAP3K6 Ref.12 Ref.18 Ref.31 Ref.35 Ref.40 Ref.43

Modified residue

842

1

Phosphothreonine; by autocatalysis Ref.43

Modified residue

958

1

Phosphoserine

Modified residue

966

1

Phosphoserine Ref.23 Ref.25 Ref.40

Modified residue

976

1

Phosphothreonine By similarity

Modified residue

1029

1

Phosphoserine Ref.36 Ref.37

Modified residue

1033

1

Phosphoserine Ref.25 Ref.36 Ref.37 Ref.38 Ref.40

Natural variations

Natural variant

1006

1

G → R. Ref.44
Corresponds to variant rs45626535 [ dbSNP | Ensembl ].

VAR_040693

Natural variant

1214

1

I → T. Ref.44
Corresponds to variant rs56379668 [ dbSNP | Ensembl ].

VAR_040694

Natural variant

1250

1

I → V. Ref.44
Corresponds to variant rs35551087 [ dbSNP | Ensembl ].

VAR_040695

Natural variant

1314

1

T → I. Ref.44
Corresponds to variant rs45599539 [ dbSNP | Ensembl ].

VAR_040696

Natural variant

1315

1

D → N. Ref.44
Corresponds to variant rs41288957 [ dbSNP | Ensembl ].

VAR_040697

Experimental info

Mutagenesis

709

1

K → M: Loss of kinase activity. Inhibits activation of JNK and apoptosis mediated by TNFRSF6 and DAXX. Ref.7 Ref.31

Mutagenesis

709

1

K → R: Loss of kinase activity. Abolishes DAXX-mediated apoptosis. Ref.7 Ref.31

Mutagenesis

966

1

S → A: Enhanced induction of apoptosis, increased kinase activity, and loss of YWHAG binding. Ref.8 Ref.25

Mutagenesis

1033

1

S → A: Enhanced induction of apoptosis and increased kinase activity. Ref.25

Secondary structure

1

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1374

Helix Strand Turn

Details...

Beta strand

673 – 675

3

Beta strand

681 – 683

3

Beta strand

685 – 688

4

Beta strand

690 – 699

10

Turn

700 – 702

3

Beta strand

705 – 712

8

Helix

720 – 730

11

Beta strand

740 – 746

7

Beta strand

749 – 755

7

Beta strand

758 – 761

4

Helix

762 – 768

7

Helix

777 – 796

20

Helix

806 – 808

3

Beta strand

809 – 812

4

Turn

813 – 815

3

Beta strand

818 – 820

3

Turn

823 – 825

3

Beta strand

827 – 829

3

Helix

843 – 845

3

Helix

848 – 853

6

Helix

854 – 857

4

Helix

860 – 876

17

Helix

882 – 884

3

Helix

887 – 897

11

Helix

909 – 917

9

Turn

923 – 925

3

Helix

929 – 933

5

Helix

936 – 938

3

Sequences

	Sequence		Length	Mass (Da)
	Q99683 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 265BDC65968AF985	FASTA	1,374	154,537
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.
[34]	"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.
[35]	"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.
[36]	"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, MASS SPECTROMETRY. Tissue: Platelet.
[37]	"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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[38]	"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, MASS SPECTROMETRY.
[39]	"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.
[40]	"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.
[41]	"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.
[42]	"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.
[43]	"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.
[44]	"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. , 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.

IPI

IPI00412433.

RefSeq

NP_005914.1. NM_005923.3.

UniGene

Hs.186486.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CLQ	X-ray	2.30	A/B	659-951	[»]
3VW6	X-ray	2.40	A/B	671-939	[»]

ProteinModelPortal

Q99683.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29516N.

IntAct

Q99683. 29 interactions.

MINT

MINT-99796.

STRING

9606.ENSP00000351908.

PTM databases

PhosphoSite

Q99683.

Polymorphism databases

DMDM

6685617.

Proteomic databases

PaxDb

Q99683.

PRIDE

Q99683.

Protocols and materials databases

DNASU

4217.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000359015; ENSP00000351908; ENSG00000197442.

GeneID

4217.

KEGG

hsa:4217.

UCSC

uc003qhc.3. human.

Organism-specific databases

CTD

4217.

GeneCards

GC06M136919.

HGNC

HGNC:6857. MAP3K5.

HPA

CAB007824.

MIM

602448. gene.

neXtProt

NX_Q99683.

PharmGKB

PA30601.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOVERGEN

HBG006305.

InParanoid

Q99683.

KO

K04426.

OMA

HEWNFSA.

OrthoDB

EOG4XSKP2.

PhylomeDB

Q99683.

Enzyme and pathway databases

BRENDA

2.7.12.2. 2681.

Pathway_Interaction_DB

pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
mtor_4pathway. mTOR signaling pathway.
p38_mkk3_6pathway. p38 MAPK signaling pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
tnfpathway. TNF receptor signaling pathway.

Gene expression databases

ArrayExpress

Q99683.

Bgee

Q99683.

CleanEx

HS_MAP3K5.

Genevestigator

Q99683.

GermOnline

ENSG00000197442. Homo sapiens.

Family and domain databases

InterPro

IPR025136. DUF4071.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR013761. SAM/pointed.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF13281. DUF4071. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.
SSF47769. SAM_homology. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q99683.

ChEMBL

CHEMBL5285.

ChiTaRS

MAP3K5. human.

EvolutionaryTrace

Q99683.

GenomeRNAi

4217.

NextBio

16633.

SOURCE

Search...

Entry information

Entry name

M3K5_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 143 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.