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/Smad3 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 BN, Waxman JS, Miller JR, Takemaru K, Sheldahl LC, Khlebtsova N, Fox EP, Earnest T, Moon RT . Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation . English . Developmental Cell . 2 . 4 . 449–461 . April 2002 . 11970895 . 10.1016/S1534-5807(02)00140-5 . free .
  3. Esposito M, Fang C, Cook KC, Park N, Wei Y, Spadazzi C, Bracha D, Gunaratna RT, Laevsky G, DeCoste CJ, Slabodkin H, Brangwynne CP, Cristea IM, Kang Y . TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis . Nature Cell Biology . 23 . 3 . 257–267 . March 2021 . 33723425 . 7970447 . 10.1038/s41556-021-00641-w .
  4. Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, Sunamura M, Imamura T, Miyazono K, Aburatani H . Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling . Molecular and Cellular Biology . 29 . 1 . 172–186 . January 2009 . 18955504 . 2612478 . 10.1128/MCB.01038-08 .
  5. Huang Y, Wang P, Chen H, Ding Y, Chen YG . Myc-interacting zinc-finger protein 1 positively regulates Wnt signalling by protecting Dishevelled from Dapper1-mediated degradation . The Biochemical Journal . 466 . 3 . 499–509 . March 2015 . 25558878 . 10.1042/BJ20141143 .
  6. Ma B, Cao W, Li W, Gao C, Qi Z, Zhao Y, Du J, Xue H, Peng J, Wen J, Chen H, Ning Y, Huang L, Zhang H, Gao X, Yu L, Chen YG . Dapper1 promotes autophagy by enhancing the Beclin1-Vps34-Atg14L complex formation . Cell Research . 24 . 8 . 912–924 . August 2014 . 24980960 . 4123296 . 10.1038/cr.2014.84 .
  7. Web site: AlphaFold Protein Structure Database. 2021-11-30. alphafold.ebi.ac.uk.
  8. Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, Sokol SY, McCrea PD . Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals . Developmental Cell . 11 . 5 . 683–695 . November 2006 . 17084360 . 10.1016/j.devcel.2006.09.022 . free .
  9. Zhang L, Gao X, Wen J, Ning Y, Chen YG . Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation . The Journal of Biological Chemistry . 281 . 13 . 8607–8612 . March 2006 . 16446366 . 10.1074/jbc.M600274200 . free .
  10. Gao X, Wen J, Zhang L, Li X, Ning Y, Meng A, Chen YG . Dapper1 is a nucleocytoplasmic shuttling protein that negatively modulates Wnt signaling in the nucleus . English . The Journal of Biological Chemistry . 283 . 51 . 35679–35688 . December 2008 . 18936100 . 10.1074/jbc.M804088200 . free .
  11. Chen H, Liu L, Ma B, Ma TM, Hou JJ, Xie GM, Wu W, Yang FQ, Chen YG . Protein kinase A-mediated 14-3-3 association impedes human Dapper1 to promote dishevelled degradation . The Journal of Biological Chemistry . 286 . 17 . 14870–14880 . April 2011 . 21262972 . 3083226 . 10.1074/jbc.M110.211607 . free .
  12. Kivimäe S, Yang XY, Cheyette BN . All Dact (Dapper/Frodo) scaffold proteins dimerize and exhibit conserved interactions with Vangl, Dvl, and serine/threonine kinases . BMC Biochemistry . 12 . 33 . June 2011 . 21718540 . 3141656 . 10.1186/1471-2091-12-33 . free .
  13. Web site: Saplakoglu. Yasemin. 2021-03-24. Meet the 'frodosome,' a brand new organelle. 2021-12-01. livescience.com. en.
  14. Yu C, Lang Y, Hou C, Yang E, Ren X, Li T . Distinctive Network Topology of Phase-Separated Proteins in Human Interactome . Journal of Molecular Biology . 434 . 1 . 167292 . January 2022 . 34624295 . 10.1016/j.jmb.2021.167292 . 238529546 .
  15. Web site: OMIM Entry - # 617466 - TOWNES-BROCKS SYNDROME 2; TBS2. 2021-12-01. omim.org. en-us.

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