MAP3K5 (mitogen-activated protein kinase kinase kinase 5)

Gene

• Entrez ID: 4217
• Gene name: Mitogen-activated protein kinase kinase kinase 5
• Gene symbol: MAP3K5
• Synonyms: ASK1, MAPKKK5, MEKK5
• Chromosome: 6
• Chromosome location: 6q23.3
• Summary: Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT039091	hsa-miR-769-3p	CLASH	23622248
MIRT053208	hsa-miR-20a-5p	Luciferase reporter assay, qRT-PCR, Western blot	23087182
MIRT440282	hsa-miR-218-5p	HITS-CLIP	23212916
MIRT556286	hsa-miR-1303	PAR-CLIP	21572407
MIRT556286	hsa-miR-1303	PAR-CLIP	27292025
MIRT556287	hsa-miR-5191	PAR-CLIP	21572407
MIRT556287	hsa-miR-5191	PAR-CLIP	27292025
MIRT556288	hsa-miR-4753-3p	PAR-CLIP	21572407
MIRT556288	hsa-miR-4753-3p	PAR-CLIP	27292025
MIRT556289	hsa-miR-642b-3p	PAR-CLIP	21572407
MIRT556289	hsa-miR-642b-3p	PAR-CLIP	27292025
MIRT556290	hsa-miR-642a-3p	PAR-CLIP	21572407
MIRT556290	hsa-miR-642a-3p	PAR-CLIP	27292025
MIRT556291	hsa-miR-302d-5p	PAR-CLIP	21572407
MIRT556291	hsa-miR-302d-5p	PAR-CLIP	27292025
MIRT556292	hsa-miR-302b-5p	PAR-CLIP	21572407
MIRT556292	hsa-miR-302b-5p	PAR-CLIP	27292025
MIRT556293	hsa-miR-130b-5p	PAR-CLIP	21572407
MIRT556293	hsa-miR-130b-5p	PAR-CLIP	27292025
MIRT556294	hsa-miR-208b-5p	PAR-CLIP	21572407
MIRT556294	hsa-miR-208b-5p	PAR-CLIP	27292025
MIRT556295	hsa-miR-208a-5p	PAR-CLIP	21572407
MIRT556295	hsa-miR-208a-5p	PAR-CLIP	27292025
MIRT556296	hsa-miR-4517	PAR-CLIP	21572407
MIRT556296	hsa-miR-4517	PAR-CLIP	27292025
MIRT556297	hsa-miR-425-5p	PAR-CLIP	21572407
MIRT556297	hsa-miR-425-5p	PAR-CLIP	27292025
MIRT733517	hsa-miR-301a-3p	Luciferase reporter assay, qRT-PCR, Western blot	27775615
MIRT735026	hsa-miR-19a-3p	Luciferase reporter assay, Western blot	25982447
MIRT735117	hsa-miR-1224-3p	Immunofluorescence	26148557
MIRT772223	hsa-miR-4775	PAR-CLIP	27292025
MIRT775356	hsa-miR-590-3p	PAR-CLIP	27292025

Transcription factors

Transcription factor	Regulation	Reference
E2F1	Activation	16476732;17287612
E2F1	Unknown	16512785;19610065
E2F2	Unknown	16512785
E2F3	Unknown	16512785
E2F4	Unknown	16512785
RB1	Unknown	19610065

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000165	Process	MAPK cascade	IDA	17210579, 21771788
GO:0000186	Process	Activation of MAPKK activity	IBA	21873635
GO:0000186	Process	Activation of MAPKK activity	IDA	11959862
GO:0000287	Function	Magnesium ion binding	IDA	17210579
GO:0002931	Process	Response to ischemia	IEA
GO:0004672	Function	Protein kinase activity	IBA	21873635
GO:0004672	Function	Protein kinase activity	IDA	11096076, 21771788
GO:0004674	Function	Protein serine/threonine kinase activity	TAS
GO:0004709	Function	MAP kinase kinase kinase activity	IBA	21873635
GO:0004709	Function	MAP kinase kinase kinase activity	IDA	17210579
GO:0005515	Function	Protein binding	IPI	9743501, 11003656, 11154276, 11298454, 11495919, 12556535, 12813029, 14557248, 14761963, 15023544, 15246877, 15983381, 16049941, 16449798, 16636664, 16648474, 17210579, 17389591, 17700517, 17761141, 19590015, 19782076, 19805025, 21496457, 21771788, 22609355, 25241761, 25852190, 2609
GO:0005524	Function	ATP binding	IDA	17210579
GO:0005737	Component	Cytoplasm	IDA	26095851
GO:0005829	Component	Cytosol	TAS
GO:0006468	Process	Protein phosphorylation	IDA	11096076, 15983381
GO:0007254	Process	JNK cascade	IDA	21771788
GO:0007257	Process	Activation of JUN kinase activity	TAS	8974401
GO:0008631	Process	Intrinsic apoptotic signaling pathway in response to oxidative stress	IBA	21873635
GO:0008631	Process	Intrinsic apoptotic signaling pathway in response to oxidative stress	IDA	21771788, 26095851
GO:0009897	Component	External side of plasma membrane	IEA
GO:0010666	Process	Positive regulation of cardiac muscle cell apoptotic process	IEA
GO:0016032	Process	Viral process	IEA
GO:0019901	Function	Protein kinase binding	IEA
GO:0019903	Function	Protein phosphatase binding	IPI	11959862, 20674765
GO:0019904	Function	Protein domain specific binding	IPI	11096076
GO:0032991	Component	Protein-containing complex	IMP	11096076
GO:0033554	Process	Cellular response to stress	IBA	21873635
GO:0034198	Process	Cellular response to amino acid starvation	IDA	11096076
GO:0034976	Process	Response to endoplasmic reticulum stress	IMP	23000344
GO:0038066	Process	P38MAPK cascade	IEA
GO:0042060	Process	Wound healing	IEA
GO:0042802	Function	Identical protein binding	IPI	9743501, 17937911, 19805025
GO:0042803	Function	Protein homodimerization activity	IDA	11920685
GO:0043065	Process	Positive regulation of apoptotic process	IDA	21771788
GO:0043280	Process	Positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	IDA	20674765
GO:0043507	Process	Positive regulation of JUN kinase activity	IMP	23000344
GO:0045087	Process	Innate immune response	IEA
GO:0045663	Process	Positive regulation of myoblast differentiation	IEA
GO:0045893	Process	Positive regulation of transcription, DNA-templated	IDA	11096076
GO:0046330	Process	Positive regulation of JNK cascade	ISS
GO:0051403	Process	Stress-activated MAPK cascade	IDA	11096076
GO:0070059	Process	Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ISS
GO:0070301	Process	Cellular response to hydrogen peroxide	IDA	20674765
GO:0071356	Process	Cellular response to tumor necrosis factor	IEA
GO:0072577	Process	Endothelial cell apoptotic process	IEA
GO:0097190	Process	Apoptotic signaling pathway	TAS	8974401
GO:0097300	Process	Programmed necrotic cell death	IEA
GO:1900745	Process	Positive regulation of p38MAPK cascade	IEA
GO:1901216	Process	Positive regulation of neuron death	IGI	15983381
GO:1901216	Process	Positive regulation of neuron death	ISS
GO:1902170	Process	Cellular response to reactive nitrogen species	IEA
GO:1902911	Component	Protein kinase complex	IDA	15983381
GO:1904707	Process	Positive regulation of vascular associated smooth muscle cell proliferation	IEA
GO:1990604	Component	IRE1-TRAF2-ASK1 complex	IDA	12050113, 23000344

Other IDs

• MIM: 602448
• HGNC: 6857
• e!Ensembl: ENSG00000197442

Protein

• UniProt ID: Q99683
• Protein name: Mitogen-activated protein kinase kinase kinase 5 (EC 2.7.11.25) (Apoptosis signal-regulating kinase 1) (ASK-1) (MAPK/ERK kinase kinase 5) (MEK kinase 5) (MEKK 5)
• Protein 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).
• PDB: 2CLQ, 3VW6, 4BF2, 4BHN, 4BIB, 4BIC, 4BID, 4BIE, 5ULM, 5UOR, 5UOX, 5UP3, 5V19, 5V24, 5VIL, 5VIO, 6E2M, 6E2N, 6E2O, 6EJL, 6OYT, 6OYW, 6VRE, 6XIH
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF13281	DUF4071	165 → 545	Domain of unknown function (DUF4071)	Family
  PF19039	ASK_PH	555 → 654	ASK kinase PH domain	Domain
  PF00069	Pkinase	682 → 938	Protein kinase domain	Domain

• Sequence:

  MSTEADEGITFSVPPFAPSGFCTIPEGGICRRGGAAAVGEGEEHQLPPPPPGSFWNVESA
  AAPGIGCPAATSSSSATRGRGSSVGGGSRRTTVAYVINEASQGQLVVAESEALQSLREAC
  ETVGATLETLHFGKLDFGETTVLDRFYNADIAVVEMSDAFRQPSLFYHLGVRESFSMANN
  IILYCDTNSDSLQSLKEIICQKNTMCTGNYTFVPYMITPHNKVYCCDSSFMKGLTELMQP
  NFELLLGPICLPLVDRFIQLLKVAQASSSQYFRESILNDIRKARNLYTGKELAAELARIR
  QRVDNIEVLTADIVINLLLSYRDIQDYDSIVKLVETLEKLPTFDLASHHHVKFHYAFALN
  RRNLPGDRAKALDIMIPMVQSEGQVASDMYCLVGRIYKDMFLDSNFTDTESRDHGASWFK
  KAFESEPTLQSGINYAVLLLAAGHQFESSFELRKVGVKLSSLLGKKGNLEKLQSYWEVGF
  FLGASVLANDHMRVIQASEKLFKLKTPAWYLKSIVETILIYKHFVKLTTEQPVAKQELVD
  FWMDFLVEATKTDVTVVRFPVLILEPTKIYQPSYLSINNEVEEKTISIWHVLPDDKKGIH
  EWNFSASSVRGVSISKFEERCCFLYVLHNSDDFQIYFCTELHCKKFFEMVNTITEEKGRS
  TEEGDCESDLLEYDYEYDENGDRVVLGKGTYGIVYAGRDLSNQVRIAIKEIPERDSRYSQ
  PLHEEIALHKHLKHKNIVQYLGSFSENGFIKIFMEQVPGGSLSALLRSKWGPLKDNEQTI
  GFYTKQILEGLKYLHDNQIVHRDIKGDNVLINTYSGVLKISDFGTSKRLAGINPCTETFT
  GTLQYMAPEIIDKGPRGYGKAADIWSLGCTIIEMATGKPPFYELGEPQAAMFKVGMFKVH
  PEIPESMSAEAKAFILKCFEPDPDKRACANDLLVDEFLKVSSKKKKTQPKLSALSAGSNE
  YLRSISLPVPVLVEDTSSSSEYGSVSPDTELKVDPFSFKTRAKSCGERDVKGIRTLFLGI
  PDENFEDHSAPPSPEEKDSGFFMLRKDSERRATLHRILTEDQDKIVRNLMESLAQGAEEP
  KLKWEHITTLIASLREFVRSTDRKIIATTLSKLKLELDFDSHGISQVQVVLFGFQDAVNK
  VLRNHNIKPHWMFALDSIIRKAVQTAITILVPELRPHFSLASESDTADQEDLDVEDDHEE
  QPSNQTVRRPQAVIEDAVATSGVSTLSSTVSHDSQSAHRSLNVQLGRMKIETNRLLEELV
  RKEKELQALLHRAIEEKDQEIKHLKLKSQPIEIPELPVFHLNSSGTNTEDSELTDWLRVN
  GADEDTISRFLAEDYTLLDVLYYVTRDDLKCLRLRGGMLCTLWKAIIDFRNKQT

• Sequence length: 1374