ID:M3K5_HUMAN DESCRIPTION: RecName: Full=Mitogen-activated protein kinase kinase kinase 5; EC=2.7.11.25; AltName: Full=Apoptosis signal-regulating kinase 1; Short=ASK-1; AltName: Full=MAPK/ERK kinase kinase 5; Short=MEK kinase 5; Short=MEKK 5; 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). 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. SUBUNIT: 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. INTERACTION: P31749:AKT1; NbExp=2; IntAct=EBI-476263, EBI-296087; Q9UER7:DAXX; NbExp=6; IntAct=EBI-476263, EBI-77321; P46734:MAP2K3; NbExp=2; IntAct=EBI-476263, EBI-602462; Q9WTR2:Map3k6 (xeno); NbExp=3; IntAct=EBI-476263, EBI-1254790; P10599:TXN; NbExp=2; IntAct=EBI-476263, EBI-594644; P31946:YWHAB; NbExp=3; IntAct=EBI-476263, EBI-359815; P63104:YWHAZ; NbExp=2; IntAct=EBI-476263, EBI-347088; Q969S3:ZNF622; NbExp=14; IntAct=EBI-476263, EBI-2687480; 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. TISSUE SPECIFICITY: Abundantly expressed in heart and pancreas. INDUCTION: By TNF. Inhibited by HIV-1 Nef. PTM: 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. PTM: Ubiquitinated. Tumor necrosis factor (TNF) induces TNFR2- dependent ubiquitination leading to proteasomal degradation. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q99683
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000165 MAPK cascade GO:0000186 activation of MAPKK activity GO:0000187 activation of MAPK activity GO:0001934 positive regulation of protein phosphorylation GO:0002376 immune system process GO:0002931 response to ischemia GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007254 JNK cascade GO:0007257 activation of JUN kinase activity GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress GO:0010666 positive regulation of cardiac muscle cell apoptotic process GO:0010941 regulation of cell death GO:0016032 viral process GO:0016310 phosphorylation GO:0034198 cellular response to amino acid starvation GO:0034976 response to endoplasmic reticulum stress GO:0038066 p38MAPK cascade GO:0042060 wound healing GO:0043065 positive regulation of apoptotic process GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043507 positive regulation of JUN kinase activity GO:0045087 innate immune response GO:0045663 positive regulation of myoblast differentiation GO:0045893 positive regulation of transcription, DNA-templated GO:0046330 positive regulation of JNK cascade GO:0051403 stress-activated MAPK cascade GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress GO:0070301 cellular response to hydrogen peroxide GO:0071356 cellular response to tumor necrosis factor GO:0072577 endothelial cell apoptotic process GO:0097190 apoptotic signaling pathway GO:0097300 programmed necrotic cell death GO:1900745 positive regulation of p38MAPK cascade GO:1901216 positive regulation of neuron death GO:1902170 cellular response to reactive nitrogen species GO:1904707 positive regulation of vascular smooth muscle cell proliferation
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
