O35099 (M3K5_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 123. History...
Names and origin
|Protein names||Recommended name:|
Mitogen-activated protein kinase kinase kinase 5
Apoptosis signal-regulating kinase 1
MAPK/ERK kinase kinase 5
Short name=MEK kinase 5
Short name=MEKK 5
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||1380 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). Ref.4 Ref.6 Ref.7 Ref.8 Ref.9
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
Activated by various stressors, including oxidative stress, endoplasmic reticulum stress, and calcium overload, as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) and lipopolysaccharide (LPS). Homophilic association of MAP3K5/ASK1 through the C-terminal coiled-coil domains and the heteromeric complex formation of MAP3K5/ASK1 with the reduced form of thioredoxin (TXN), constitutes an inactive form of the kinase. Upon ROS-induced dissociation of TXN from MAP3K5/ASK1, TRAF2 and TRAF6 are reciprocally recruited to MAP3K5/ASK1 and form the active MAP3K5/ASK1 signalosome, in which TRAF2 and TRAF6 appear to facilitate the active configuration of MAP3K5/ASK1. MAP3K5/ASK1 activity is also regulated through several phosphorylation and dephosphorylation events. Thr-845 is an activating phosphorylation site that is autophosphorylated and phosphorylated by MAP3K6/ASK2 and dephosphorylated by PPP5C. Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2. Phosphorylation of Ser-973 induces association of MAP3K5/ASK1 with the 14-3-3 family proteins, which suppresses MAP3K5/ASK1 activity. Calcium/calmodulin-activated protein phosphatase calcineurin (PPP3CA) has been shown to directly dephosphorylate this site. SOCS1 binds to ASK1 by recognizing phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells. Also dephosphorylated and activated by PGAM5. Contains an N-terminal autoinhibitory domain. Ref.5 Ref.7 Ref.9
Homodimer when inactive By similarity. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a cytoplasmic complex made of HIPK1, DAB2IP and MAP3K5 in response to TNF By similarity. This complex formation promotes MAP3K5-JNK activation and subsequent apoptosis By similarity. Interacts with SOCS1 which recognizes phosphorylation of Tyr-725 and induces MAP3K5/ASK1 degradation in endothelial cells By similarity. Interacts with the 14-3-3 family proteins such as YWHAB, YWHAE, YWHAQ, YWHAH, YWHAZ and SFN By similarity. Interacts with ARRB2, BIRC2, DAB2IP, IGF1R, MAP3K6/ASK2, PIM1, PGAM5, PPP5C, SOCS1, STUB1, TRAF2 and TXN By similarity. Interacts with ERN1 in a TRAF2-dependent manner By similarity. Interacts with calcineurin subunit PPP3R1, PPM1L and TRAF6. Interacts (via N-terminus) with RAF1 and this interaction inhibits the proapoptotic function of MAP3K5. Interacts with DAB2IP (via N-terminus C2 domain); the interaction occurs in a TNF-alpha-dependent manner By similarity.Interacts with DUSP13/DUSP13A; may positively regulate apoptosis By similarity. Ref.7 Ref.9 Ref.10 Ref.14
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.
Expressed in various adult mouse tissues including heart, brain, lung, liver and kidney. Ref.1
Ser-90 and Ser-1040 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1 and AKT2 By similarity. Phosphorylated at Ser-973 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity By similarity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5 By similarity. Phosphorylated at Thr-845 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-845 is dephosphorylated by PPP5C. Ref.5 Ref.9 Ref.11 Ref.14
Ubiquitinated By similarity. Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination leading to proteasomal degradation By similarity.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 1380||1380||Mitogen-activated protein kinase kinase kinase 5||PRO_0000086250|
|Domain||687 – 945||259||Protein kinase|
|Nucleotide binding||693 – 701||9||ATP By similarity|
|Coiled coil||1252 – 1292||41||Potential|
|Active site||810||1||Proton acceptor By similarity|
|Binding site||716||1||ATP By similarity|
Amino acid modifications
|Modified residue||90||1||Phosphoserine; by PIM1, PKB/AKT1 and PKB/AKT2 By similarity|
|Modified residue||725||1||Phosphotyrosine By similarity|
|Modified residue||820||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||845||1||Phosphothreonine; by autocatalysis, MELK and MAP3K6 Ref.5 Ref.11 Ref.14|
|Modified residue||849||1||Phosphothreonine; by autocatalysis Ref.5|
|Modified residue||965||1||Phosphoserine By similarity|
|Modified residue||973||1||Phosphoserine By similarity|
|Modified residue||1036||1||Phosphoserine By similarity|
|Modified residue||1040||1||Phosphoserine By similarity|
|Sequence conflict||166||1||A → T in BAA23648. Ref.1|
|Sequence conflict||368 – 370||3||RRN → TRT in BAA23648. Ref.1|
|Sequence conflict||1090||1||K → N in BAA23648. Ref.1|
|||"Molecular cloning and characterization of the mouse apoptosis signal-regulating kinase 1."|
Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.
Biochem. Biophys. Res. Commun. 239:905-910(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
|||Tobiume K., Inage T., Takeda K., Enomoto S., Miyazono K., Ichijo H.|
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION TO 22-26; 123; 273; 755; 1001-1011; 1220-1222 AND 1274-1280.
|||"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].
|||"ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis."|
Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., Minowa O., Miyazono K., Noda T., Ichijo H.
EMBO Rep. 2:222-228(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer."|
Tobiume K., Saitoh M., Ichijo H.
J. Cell. Physiol. 191:95-104(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-845 AND THR-849, ENZYME REGULATION.
|||"Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation."|
Takeda K., Matsuzawa A., Nishitoh H., Tobiume K., Kishida S., Ninomiya-Tsuji J., Matsumoto K., Ichijo H.
EMBO Rep. 5:161-166(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity."|
Matsuzawa A., Saegusa K., Noguchi T., Sadamitsu C., Nishitoh H., Nagai S., Koyasu S., Matsumoto K., Takeda K., Ichijo H.
Nat. Immunol. 6:587-592(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, INTERACTION WITH TRAF6.
|||"A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation."|
Rubiolo C., Piazzolla D., Meissl K., Beug H., Huber J.C., Kolbus A., Baccarini M.
Blood 108:152-159(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth."|
Liu Q., Wilkins B.J., Lee Y.J., Ichijo H., Molkentin J.D.
Mol. Cell. Biol. 26:3785-3797(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP3R1, PHOSPHORYLATION AT SER-973, ENZYME REGULATION, FUNCTION.
|||"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.
|||"Murine protein serine/threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr 838 phosphorylation."|
Jung H., Seong H.A., Ha H.
J. Biol. Chem. 283:34541-34553(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-845.
|||"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.
|||"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.
|||"S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation."|
Yamaguchi F., Umeda Y., Shimamoto S., Tsuchiya M., Tokumitsu H., Tokuda M., Kobayashi R.
J. Biol. Chem. 287:13787-13798(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPP5C, PHOSPHORYLATION AT THR-845, DEPHOSPHORYLATION AT THR-845 BY PPP5C.
|+||Additional computationally mapped references.|
|AB006787 mRNA. Translation: BAA23648.3.|
BC116627 mRNA. Translation: AAI16628.1.
BC133697 mRNA. Translation: AAI33698.1.
|RefSeq||NP_032606.4. NM_008580.4. |
3D structure databases
|SMR||O35099. Positions 648-947. |
Protein-protein interaction databases
|BioGrid||204961. 7 interactions.|
|IntAct||O35099. 6 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000095806; ENSMUSP00000093485; ENSMUSG00000071369. |
|UCSC||uc007enm.2. mouse. |
|MGI||MGI:1346876. Map3k5. |
Enzyme and pathway databases
|BRENDA||18.104.22.168. 3474. |
Gene expression databases
Family and domain databases
|InterPro||IPR025136. DUF4071. |
|Pfam||PF13281. DUF4071. 1 hit. |
PF00069. Pkinase. 1 hit.
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF47769. SSF47769. 1 hit. |
SSF56112. SSF56112. 1 hit.
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: O35099|
Secondary accession number(s): Q14AY5
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|