ASK1

Mechanism of activation

Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator. TRAF2 and TRAF6 are then recruited to ASK1 to form a larger molecular mass complex. Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845.

ASK1 gene transcription can be induced by inflammatory cytokines such as IL-1 and TNF-α through the activation of the NF-kb protein RelA. Interestingly, TNF-α is also able to stabilize the ASK1 protein through deubiquitination. Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as post-transcriptional.

Interactions

ASK1 has been shown to interact with:

• C-Raf,
• CDC25A,
• DAXX,
• DUSP19,
• EIF2AK2,
• GADD45B,
• HSPA1A,
• MAP2K6,
• MAP3K7 and
• MAPK8IP3,
• PDCD6,
• PPP5C,
• RB1CC1,
• TRAF2,
• TRAF5, and
• TRAF6.

References

References

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2. (May 2018). "Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis". Biochemical Pharmacology.
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4. "Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5".
5. (October 2009). "CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1". Proceedings of the National Academy of Sciences of the United States of America.
6. (November 2005). "Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death". The Journal of Biological Chemistry.
7. (December 2007). "Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1". Molecular and Cellular Biology.
8. (March 2006). "SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation". The Journal of Biological Chemistry.
9. (July 2001). "Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism". Proceedings of the National Academy of Sciences of the United States of America.
10. (July 2001). "The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1". Molecular and Cellular Biology.
11. (September 1998). "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx". Science.
12. (June 2002). "Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway". The Journal of Biological Chemistry.
13. (December 2002). "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". European Journal of Biochemistry.
14. (February 2004). "Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2". Nature Cell Biology.
15. (November 2002). "Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1". Molecular and Cellular Biology.
16. (June 2003). "Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)". Molecular Cell.
17. (October 2002). "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade". The Journal of Biological Chemistry.
18. (October 2002). "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation". FEBS Letters.
19. (November 2001). "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress". The EMBO Journal.
20. (October 2006). "Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways". The Journal of Cell Biology.
21. (September 1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Molecular Cell.
22. (October 2000). "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". The Journal of Biological Chemistry.
23. (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene.