MAP3K5 - Mitogen-activated protein kinase kinase kinase 5 - human protein (Function)
 
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MAP3K5 »  Mitogen-activated protein kinase kinase kinase 5   [ EC 2.7.11.25 ]
 
Protein also known as:  Apoptosis signal-regulating kinase 1 (ASK-1).
Gene name:  MAP3K5
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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).  
18
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
1
  • IDAUniProtKB
Cysteine-type endopeptidase activator activity involved in apoptotic processdefinition[GO:0008656]  
1
  • IDAUniProtKB
Magnesium ion bindingdefinition[GO:0000287]  
1
  • IDAUniProtKB
MAP kinase kinase kinase activitydefinition[GO:0004709]  
1
  • IDAUniProtKB
Protein bindingdefinition[GO:0005515]  
17
  • IPIIntAct
  • IPIUniProtKB
Protein homodimerization activitydefinition[GO:0042803]  
1
  • IDAUniProtKB
Protein kinase activitydefinition[GO:0004672]  
1
  • IDAUniProtKB
Protein kinase bindingdefinition[GO:0019901] silver  
  • IEAOrtholog Compara
Protein phosphatase bindingdefinition[GO:0019903]  
2
  • IPIBHF-UCL
GO biological process 
Activation of cysteine-type endopeptidase activity involved in apoptotic processdefinition[GO:0006919]  
1
  • IDAGOC
Activation of JUN kinase activitydefinition[GO:0007257]  
1
  • TASPINC
Activation of MAPKK activitydefinition[GO:0000186]  
1
  • IDABHF-UCL
Apoptotic signaling pathwaydefinition[GO:0097190]  
1
  • TASPINC
Cellular response to hydrogen peroxidedefinition[GO:0070301]  
1
  • IDABHF-UCL
Innate immune responsedefinition[GO:0045087]  
  • IEAUniProtKB KW
Intrinsic apoptotic signaling pathway in response to oxidative stressdefinition[GO:0008631]  
1
  • IDAUniProtKB
JNK cascadedefinition[GO:0007254]  
1
  • IDAUniProtKB
MAPK cascadedefinition[GO:0000165]  
2
  • IDAUniProtKB
Positive regulation of apoptotic processdefinition[GO:0043065]  
1
  • IDAUniProtKB
Positive regulation of cell deathdefinition[GO:0010942]  
1
  • IGIParkinsonsUK-UCL
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic processdefinition[GO:0043280]  
1
  • IDABHF-UCL
Response to ischemiadefinition[GO:0002931] silver  
  • IEAOrtholog Compara
Viral processdefinition[GO:0016032]  
  • IEAUniProtKB KW
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.25: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It requires the following cofactor
Magnesium.  
  • CuratedUniProtKB
It is regulated in the following manner
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.  
14
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Amyotrophic lateral sclerosis (ALS)  hsa05014+4217  
MAPK signaling pathway  hsa04010+4217  
Neurotrophin signaling pathway  hsa04722+4217  
Protein processing in endoplasmic reticulum  hsa04141+4217  
According to Reactome, this protein belongs to the following pathway:
Cellular responses to stress  REACT_120956  
 

Keywords

Biological process 
Apoptosis  definition   [KW-0053]
Host-virus interaction  definition   [KW-0945]
Immunity  definition   [KW-0391]
Innate immunity  definition   [KW-0399]
Stress response  definition   [KW-0346]
Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: ASK1
GenomeRNAi: 4217
PRO: PR:Q99683
Chemistry
GuidetoPHARMACOLOGY: 2080