Dishevelled binding antagonist of beta catenin 1

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Dact1 organelle in a breast cancer cell
A holotomographic rendering of refractive index across breast cancer cells with Dact1-TdTomato fluorescence superimposed (in red) demonstrates the Dact1-scaffolded biomolecular condensate.

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 structure
Google DeepMind's Alphafold prediction of the human Dact1 3D structure

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,[2] 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.[3] 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][3] 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][3]

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]

References

  1. ^ "DACT1 dishevelled binding antagonist of beta catenin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-11-30.
  2. ^ a b 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. 2 (4): 449–461. doi:10.1016/S1534-5807(02)00140-5. ISSN 1534-5807. PMID 11970895.
  3. ^ a b c d e f g 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. 23 (3): 257–267. doi:10.1038/s41556-021-00641-w. ISSN 1476-4679. PMC 7970447. PMID 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. doi:10.1128/MCB.01038-08. PMC 2612478. PMID 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. doi:10.1042/BJ20141143. ISSN 1470-8728. PMID 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. 24 (8): 912–924. doi:10.1038/cr.2014.84. ISSN 1748-7838. PMC 4123296. PMID 24980960.
  7. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2021-11-30.
  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. doi:10.1016/j.devcel.2006.09.022. ISSN 1534-5807. PMID 17084360.
  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. doi:10.1074/jbc.M600274200. ISSN 0021-9258. PMID 16446366.
  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. 283 (51): 35679–35688. doi:10.1074/jbc.M804088200. ISSN 0021-9258. PMID 18936100.
  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. doi:10.1074/jbc.M110.211607. ISSN 1083-351X. PMC 3083226. PMID 21262972.
  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. doi:10.1186/1471-2091-12-33. ISSN 1471-2091. PMC 3141656. PMID 21718540.
  13. ^ Saplakoglu, Yasemin (2021-03-24). "Meet the 'frodosome,' a brand new organelle". livescience.com. Retrieved 2021-12-01.
  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): 167292. doi:10.1016/j.jmb.2021.167292. ISSN 0022-2836. PMID 34624295. S2CID 238529546.
  15. ^ "OMIM Entry - # 617466 - TOWNES-BROCKS SYNDROME 2; TBS2". omim.org. Retrieved 2021-12-01.
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