Disease relevance of MAP3K5

• First, in a rapid response hypoxia facilitates the association of endogenous PP5 with ASK-1 [1].
• ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications [2].
• Direct binding of apoptosis signal-regulating kinase 1 to retinoblastoma protein: novel links between apoptotic signaling and cell cycle machinery [3].
• Here we have investigated how mTOR regulates ASK1 signaling using p53-mutant rhabdomyosarcoma cells [4].
• In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level) [5].

High impact information on MAP3K5

• Our findings reveal a strategy by which HIV-1 Nef promotes the killing of bystander cells through the induction of FasL, while simultaneously protecting the HIV-1-infected host cell from these same pro-apoptotic signals through its interference with ASK1 function [6].
• Here we show that HIV-1 Nef associates with and inhibits apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that forms a common and key signalling intermediate in the Fas and tumour-necrosis factor-alpha (TNFalpha) death-signalling pathways [6].
• Fas activation induced Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity [7].
• Second, interaction with molecules such as Src, Raf, Erk, ASK1 and JNK3 appears to regulate several pathways that result in the activation of MAP kinases [8].
• These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases [9].

Chemical compound and disease context of MAP3K5

• Critical role of ASK1 in the 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells [10].
• Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines [11].
• Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway [12].

Biological context of MAP3K5

• Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis [13].
• The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis [13].
• Finally, we have shown that QRS inhibited the cell death induced by ASK1, and this antiapoptotic function of QRS was weakened by the deprivation of Gln [14].
• Furthermore, ASK1-dependent phosphorylation was required for JSAP1 to recruit and thereby activate JNK in response to H(2)O(2) [15].
• The apoptosis signal-regulating kinase 1 (ASK1)-JNK/p38 signaling pathway is pivotal component in cell apoptosis and can be activated by a variety of death stimuli including tumor necrosis factor (TNF) alpha and oxidative stress (reactive oxygen species) [16].

Anatomical context of MAP3K5

• In turn, the induction of differentiation with ceramide in keratinocytes caused an increase in ASK1 expression and activity [17].
• Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates hydrogen peroxide-induced apoptosis in human pulmonary vascular endothelial cells [18].
• ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats [9].
• Northern blot analysis showed that MAPKKK5 transcript is abundantly expressed in human heart and pancreas [19].
• PKR and ASK1 showed predominant cytoplasmic localization in COS-1 cells transfected with both cDNAs, and coimmunoprecipitated from the cell extracts [20].

Associations of MAP3K5 with chemical compounds

• In untransfected mammalian cells, ASK1 rapidly associates with TRAF2 in a TNF-dependent manner [21].
• AIP1 binds to the C-terminal domain of ASK1 via a lysine-rich cluster within the N-terminal C2 domain [22].
• The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal-regulating kinase (ASK) 1 [23].
• These results support the hypothesis that the GRX-ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H(2)O(2) [24].
• The results presented here indicate that ASK1 forms a complex with the IGF-IR and becomes phosphorylated on tyrosine residue(s) in a manner dependent on IGF-IR activity [25].

Physical interactions of MAP3K5

• Deletion mutants showed the C-terminal portion of apoptosis signal-regulating kinase 1 (ASK1) bound GRX, and glucose deprivation disrupted binding [24].
• Cys-250 and Cys-30 in the N-terminal domain of ASK1 are critical for binding of Trx1 and Trx2, respectively [26].
• It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway [27].
• Deletion analysis localized the Raf-1 binding site to the N-terminal regulatory fragment of ASK1 [28].
• In Rh30 cells, ASK1 was found to physically interact with protein phosphatase 5 (PP5), previously identified as a negative regulator of ASK1 [4].

Enzymatic interactions of MAP3K5

• ASK1 phosphorylates c-Jun N-terminal kinase (JNK) and elicits an apoptotic response [29].
• In contrast to 14-3-3, AIP1 binds preferentially to dephosphorylated ASK1 [22].
• Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue [30].
• AKT2 interacts with and phosphorylates ASK1 at Ser-83 resulting in inhibition of its kinase activity [31].
• BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M [32].

Regulatory relationships of MAP3K5

• The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1 [33].
• Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways [34].
• The relocalized Daxx may play an important role in glucose deprivation-induced ASK1 oligomerization [35].
• These results suggest that S-nitrosylation of Trx induces ASK1 activation [36].
• CHIP interacted with ASK1 in a TPR-dependent fashion and induced ubiquitylation and proteasome-dependent degradation of ASK1 [29].

Other interactions of MAP3K5

• Thus, ASK1 is a mediator of TRAF2-induced JNK activation [21].
• In this study, we have identified apoptosis signal-regulating kinase 1 (ASK1) as a CDC25A-interacting protein by yeast two-hybrid screening [33].
• Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade [1].
• 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 [16].
• Protein kinase D specifically mediates apoptosis signal-regulating kinase 1-JNK signaling induced by H2O2 but not tumor necrosis factor [37].
• During this reduction, the thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) became covalently associated with Ask1 [38].

Analytical, diagnostic and therapeutic context of MAP3K5

• Data from immunofluorescence staining and protein interaction assay suggest that phosphorylated Daxx may be translocated to the cytoplasm, bind to ASK1, and subsequently lead to ASK1 oligomerization [35].
• Thus, the antiapoptotic interaction of QRS with ASK1 is controlled positively by the cellular concentration of Gln and negatively by Fas ligation [14].
• Stimulation of HEK-293 cells with S-nitrosoglutathione (GSNO) for 2, 4, 8, and 16h also caused Trx S-nitrosylation, which showed straight correlation with ASK1 activation based on Western blot detection of the enzyme, immunoprecipitation assay, and measurement of its catalytic activity [36].
• Activation of ASK1 during reperfusion of ischemic spinal cord [39].
• The phosphorylation levels of ASK1, JNK, and p38 were assessed by immunoblotting proteins from animals that received 30min of ischemia followed by 1 or 24h of reperfusion [39].

References