Dishevelled binding antagonist of beta catenin 1 explained

Dishevelled binding antagonist of beta catenin 1 (Dact1, previously known as Dapper, Dpr1, Frodo) is a protein that in humans is encoded by the DACT1 gene.[1] Dact1 was originally described in 2002 as a negative regulator of Wnt signaling by binding and destabilizing Dishevelled.[2] More recent investigation into the molecular function of Dact1 has identified its principle role in the cell as a scaffold to generate membrane-less biomolecular condensates through liquid-liquid phase separation.[3] Mutations in the phase-separating regions of Dact1 lead to Townes-Brock Syndrome 2 while its overexpression is associated with bone metastasis.[3]

Regulation and function

Dact1 is regulated by the TGF-β pathway through Smad2/3 binding sites in its promoter region.[4] Dact1 is degraded through the proteasome[3] and is described as a Wnt activator,[5] a Wnt suppressor, or alternately a Wnt-independent regulator of the autophagosome.[6] The Dact1 protein is annotated with 10 intrinsically disordered domains, a nuclear localization sequence, a nuclear export sequence, a PDZ binding domain, and a coiled-coiled domain. AI-based protein folding predictions describe a highly disordered exterior calyx surrounding an ordered interior.[7] Dact1 has been reported to interact with numerous proteins including itself, Dishevelled, p120, LEF, 14-3-3 proteins, VPS34, Miz1, Vangl, and Dact2 through immunoprecipitation studies.[8] [9] [10] [11] [12] More recent studies into the role of Dact1 in forming "Frodosomes",[13] or membrane-less, organelle-like biomolecular condensates, identified a Dact1 protein signature that included many previously identified interactors as well as new proteins such as Casein Kinase 2.[14]

Health and disease

Dact1 is an essential regulator of development through its role in regulating Wnt activity and its deletion is embryonically lethal. Heterozygous mutations in Dact1 cause Townes-Brock Syndrome 2 in humans which is inherited in an autosomal dominant pattern.[15] High levels of Dact1 mRNA predicts worse outcome in breast cancer bone metastasis and is an essential protein in the bone metastatic cascade.[3]

Notes and References

  1. Web site: DACT1 dishevelled binding antagonist of beta catenin 1 [Homo sapiens (human)] - Gene - NCBI]. 2021-11-30. www.ncbi.nlm.nih.gov.
  2. Cheyette. Benjamin N. R.. Waxman. Joshua S.. Miller. Jeffrey R.. Takemaru. Ken-Ichi. Sheldahl. Laird C.. Khlebtsova. Natasha. Fox. Eric P.. Earnest. Thomas. Moon. Randall T.. 2002-04-01. Dapper, a Dishevelled-Associated Antagonist of β-Catenin and JNK Signaling, Is Required for Notochord Formation. Developmental Cell. English. 2. 4. 449–461. 10.1016/S1534-5807(02)00140-5. 1534-5807. 11970895. free.
  3. Esposito. Mark. Fang. Cao. Cook. Katelyn C.. Park. Nana. Wei. Yong. Spadazzi. Chiara. Bracha. Dan. Gunaratna. Ramesh T.. Laevsky. Gary. DeCoste. Christina J.. Slabodkin. Hannah. March 2021. TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nature Cell Biology. en. 23. 3. 257–267. 10.1038/s41556-021-00641-w. 1476-4679. 7970447. 33723425.
  4. Koinuma. Daizo. Tsutsumi. Shuichi. Kamimura. Naoko. Taniguchi. Hirokazu. Miyazawa. Keiji. Sunamura. Makoto. Imamura. Takeshi. Miyazono. Kohei. Aburatani. Hiroyuki. 2009-01-01. Chromatin Immunoprecipitation on Microarray Analysis of Smad2/3 Binding Sites Reveals Roles of ETS1 and TFAP2A in Transforming Growth Factor β Signaling. Molecular and Cellular Biology. 29. 1. 172–186. 10.1128/MCB.01038-08. 2612478. 18955504.
  5. Huang. Yongsheng. Wang. Peng. Chen. Hua. Ding. Yi. Chen. Ye-Guang. 2015-03-15. Myc-interacting zinc-finger protein 1 positively regulates Wnt signalling by protecting Dishevelled from Dapper1-mediated degradation. The Biochemical Journal. 466. 3. 499–509. 10.1042/BJ20141143. 1470-8728. 25558878.
  6. Ma. Benyu. Cao. Weipeng. Li. Wenxia. Gao. Chan. Qi. Zhen. Zhao. Yan. Du. Jun. Xue. Hua. Peng. Junya. Wen. Jun. Chen. Hua. August 2014. Dapper1 promotes autophagy by enhancing the Beclin1-Vps34-Atg14L complex formation. Cell Research. en. 24. 8. 912–924. 10.1038/cr.2014.84. 24980960. 4123296. 1748-7838.
  7. Web site: AlphaFold Protein Structure Database. 2021-11-30. alphafold.ebi.ac.uk.
  8. Park. Jae-il. Ji. Hong. Jun. Sohee. Gu. Dongmin. Hikasa. Hiroki. Li. Lei. Sokol. Sergei Y.. McCrea. Pierre D.. November 2006. Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Developmental Cell. 11. 5. 683–695. 10.1016/j.devcel.2006.09.022. 1534-5807. 17084360. free.
  9. Zhang. Long. Gao. Xia. Wen. Jun. Ning. Yuanheng. Chen. Ye-Guang. 2006-03-31. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. The Journal of Biological Chemistry. 281. 13. 8607–8612. 10.1074/jbc.M600274200. 0021-9258. 16446366. free.
  10. Gao. Xia. Wen. Jun. Zhang. Long. Li. Xiang. Ning. Yuanheng. Meng. Anming. Chen. Ye-Guang. 2008-12-19. Dapper1 Is a Nucleocytoplasmic Shuttling Protein That Negatively Modulates Wnt Signaling in the Nucleus *. Journal of Biological Chemistry. English. 283. 51. 35679–35688. 10.1074/jbc.M804088200. 0021-9258. 18936100. free.
  11. Chen. Hua. Liu. Linhua. Ma. Benyu. Ma. Ting Martin. Hou. Jun-Jie. Xie. Guo-Ming. Wu. Wei. Yang. Fu-Quan. Chen. Ye-Guang. 2011-04-29. Protein kinase A-mediated 14-3-3 association impedes human Dapper1 to promote dishevelled degradation. The Journal of Biological Chemistry. 286. 17. 14870–14880. 10.1074/jbc.M110.211607. 1083-351X. 3083226. 21262972. free.
  12. Kivimäe. Saul. Yang. Xiao Yong. Cheyette. Benjamin NR. 2011-06-30. All Dact (Dapper/Frodo) scaffold proteins dimerize and exhibit conserved interactions with Vangl, Dvl, and serine/threonine kinases. BMC Biochemistry. 12. 33. 10.1186/1471-2091-12-33. 1471-2091. 3141656. 21718540 . free .
  13. Web site: Saplakoglu. Yasemin. 2021-03-24. Meet the 'frodosome,' a brand new organelle. 2021-12-01. livescience.com. en.
  14. Yu. Chunyu. Lang. Yunzhi. Hou. Chao. Yang. Ence. Ren. Xianwen. Li. Tingting. 2021-10-06. Distinctive Network Topology of Phase-Separated Proteins in Human Interactome. Journal of Molecular Biology. 434. 1 . en. 167292. 10.1016/j.jmb.2021.167292. 34624295. 238529546. 0022-2836.
  15. Web site: OMIM Entry - # 617466 - TOWNES-BROCKS SYNDROME 2; TBS2. 2021-12-01. omim.org. en-us.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Dishevelled binding antagonist of beta catenin 1".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.