Biology:ASK1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.[1][2]

MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33.[3] and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains.[citation needed] Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.[4]

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).[5] 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.[6] 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.[7]

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.[2] Interestingly, TNF-α is also able to stabilize the ASK1 protein through deubiquitination.[8] Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as post-transcriptional.[2]

Interactions

ASK1 has been shown to interact with:


References

  1. ↑ "The roles of ASK family proteins in stress responses and diseases". Cell Communication and Signaling 7: 9. April 2009. doi:10.1186/1478-811X-7-9. PMID 19389260. 
  2. ↑ 2.0 2.1 2.2 "Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis". Biochemical Pharmacology 151: 282–290. May 2018. doi:10.1016/j.bcp.2018.01.041. PMID 29408488. 
  3. ↑ "Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5". Cytogenetics and Cell Genetics 78 (3–4): 301–3. 1997. doi:10.1159/000134677. PMID 9465908. 
  4. ↑ "Entrez Gene: MAP3K5 mitogen-activated protein kinase kinase kinase 5". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4217. 
  5. ↑ "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 106 (41): 17389–94. October 2009. doi:10.1073/pnas.0812259106. PMID 19805025. Bibcode: 2009PNAS..10617389Y. 
  6. ↑ "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 280 (44): 37033–40. November 2005. doi:10.1074/jbc.M506771200. PMID 16129676. 
  7. ↑ "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 27 (23): 8152–63. December 2007. doi:10.1128/MCB.00227-07. PMID 17724081. 
  8. ↑ "SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation". The Journal of Biological Chemistry 281 (9): 5559–66. March 2006. doi:10.1074/jbc.M512338200. PMID 16407264. 
  9. ↑ "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 98 (14): 7783–8. July 2001. doi:10.1073/pnas.141224398. PMID 11427728. Bibcode: 2001PNAS...98.7783C. 
  10. ↑ "The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1". Molecular and Cellular Biology 21 (14): 4818–28. July 2001. doi:10.1128/MCB.21.14.4818-4828.2001. PMID 11416155. 
  11. ↑ "Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx". Science 281 (5384): 1860–3. September 1998. doi:10.1126/science.281.5384.1860. PMID 9743501. Bibcode: 1998Sci...281.1860C. 
  12. ↑ "Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway". The Journal of Biological Chemistry 277 (26): 23919–26. June 2002. doi:10.1074/jbc.M200838200. PMID 11959862. 
  13. ↑ "Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways". European Journal of Biochemistry 269 (24): 6126–32. December 2002. doi:10.1046/j.1432-1033.2002.03325.x. PMID 12473108. 
  14. ↑ "Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2". Nature Cell Biology 6 (2): 146–53. February 2004. doi:10.1038/ncb1093. PMID 14743220. 
  15. ↑ "Heat shock protein hsp72 is a negative regulator of apoptosis signal-regulating kinase 1". Molecular and Cellular Biology 22 (22): 7721–30. November 2002. doi:10.1128/MCB.22.22.7721-7730.2002. PMID 12391142. 
  16. ↑ 16.0 16.1 "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress". The EMBO Journal 20 (21): 6028–36. November 2001. doi:10.1093/emboj/20.21.6028. PMID 11689443. 
  17. ↑ "Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1)". Molecular Cell 11 (6): 1491–501. June 2003. doi:10.1016/S1097-2765(03)00180-1. PMID 12820963. 
  18. ↑ 18.0 18.1 "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". The Journal of Biological Chemistry 275 (42): 32747–52. October 2000. doi:10.1074/jbc.M003042200. PMID 10921914. 
  19. ↑ "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 277 (43): 40703–9. October 2002. doi:10.1074/jbc.M202004200. PMID 12189133. 
  20. ↑ "Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation". FEBS Letters 529 (2–3): 183–7. October 2002. doi:10.1016/S0014-5793(02)03329-X. PMID 12372597. 
  21. ↑ 21.0 21.1 "Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways". The Journal of Cell Biology 175 (1): 121–33. October 2006. doi:10.1083/jcb.200604129. PMID 17015619. 
  22. ↑ 22.0 22.1 22.2 "ASK1 is essential for JNK/SAPK activation by TRAF2". Molecular Cell 2 (3): 389–95. September 1998. doi:10.1016/S1097-2765(00)80283-X. PMID 9774977. 
  23. ↑ 23.0 23.1 "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene 18 (42): 5814–20. October 1999. doi:10.1038/sj.onc.1202975. PMID 10523862. 

External links

Further reading



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