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DACT1
Identifiers
Aliases	DACT1, DAPPER, DAPPER1, DPR1, FRODO, HDPR1, THYEX3, dishevelled binding antagonist of beta catenin 1, TBS2
External IDs	OMIM: 607861; MGI: 1891740; HomoloGene: 9613; GeneCards: DACT1; OMA:DACT1 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) Band 14q23.1 Start 58,633,967 bp End 58,648,321 bp
Gene location (Mouse) Chr. Chromosome 12 (mouse) Band 12|12 C3 Start 71,356,658 bp End 71,366,881 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right coronary artery gallbladder ganglionic eminence ascending aorta left coronary artery tibial nerve cerebellar cortex cerebellar hemisphere cartilage tissue Descending thoracic aorta Top expressed in condyle sciatic nerve trigeminal ganglion stroma of kidney fossa medial ganglionic eminence genital tubercle tail of embryo abdominal wall endocardial cushion More reference expression data BioGPS n/a
Gene ontology Molecular function beta-catenin binding protein kinase A binding histone deacetylase binding delta-catenin binding protein binding protein kinase C binding Cellular component cytoplasm cytosol synapse nucleoplasm cell junction nucleus beta-catenin destruction complex Biological process regulation of protein stability positive regulation of protein catabolic process regulation of Wnt signaling pathway, planar cell polarity pathway negative regulation of Wnt signaling pathway regulation of nodal signaling pathway negative regulation of transcription by RNA polymerase II Wnt signaling pathway negative regulation of protein binding embryonic hindgut morphogenesis nervous system development negative regulation of G1/S transition of mitotic cell cycle multicellular organism development positive regulation of Wnt signaling pathway negative regulation of JNK cascade negative regulation of beta-catenin-TCF complex assembly neural tube development positive regulation of protein binding negative regulation of canonical Wnt signaling pathway regulation of canonical Wnt signaling pathway positive regulation of canonical Wnt signaling pathway regulation of Wnt signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51339 59036 Ensembl ENSG00000165617 ENSMUSG00000044548 UniProt Q9NYF0 Q8R4A3 RefSeq (mRNA) NM_001079520 NM_016651 NM_001190466 NM_021532 RefSeq (protein) NP_001072988 NP_057735 NP_001177395 NP_067507 Location (UCSC) Chr 14: 58.63 – 58.65 Mb Chr 12: 71.36 – 71.37 Mb PubMed search
Wikidata
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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. Dact1 was originally described in 2002 as a negative regulator of Wnt signaling by binding and destabilizing Dishevelled. 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. Mutations in the phase-separating regions of Dact1 lead to Townes-Brock Syndrome 2 while its overexpression is associated with bone metastasis.

Regulation and function

Dact1 is regulated by the TGF-β pathway through Smad2/Smad3 binding sites in its promoter region. Dact1 is degraded through the proteasome and is described as a Wnt activator, a Wnt suppressor, or alternately a Wnt-independent regulator of the autophagosome. 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. 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. More recent studies into the role of Dact1 in forming "Frodosomes", 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.

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. High levels of Dact1 mRNA predicts worse outcome in breast cancer bone metastasis and is an essential protein in the bone metastatic cascade.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000165617 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000044548 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "DACT1 dishevelled binding antagonist of beta catenin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-11-30.
6. ^ Cheyette BN, Waxman JS, Miller JR, Takemaru K, Sheldahl LC, Khlebtsova N, et al. (April 2002). "Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation". Developmental Cell. 2 (4): 449–461. doi:10.1016/S1534-5807(02)00140-5. PMID 11970895.
7. ^ Esposito M, Fang C, Cook KC, Park N, Wei Y, Spadazzi C, et al. (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. PMC 7970447. PMID 33723425.
8. Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, Sunamura M, et al. (January 2009). "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. doi:10.1128/MCB.01038-08. PMC 2612478. PMID 18955504.
9. Huang Y, Wang P, Chen H, Ding Y, Chen YG (March 2015). "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. PMID 25558878.
10. Ma B, Cao W, Li W, Gao C, Qi Z, Zhao Y, et al. (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. PMC 4123296. PMID 24980960.
11. "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2021-11-30.
12. Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, et al. (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. PMID 17084360.
13. Zhang L, Gao X, Wen J, Ning Y, Chen YG (March 2006). "Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation". The Journal of Biological Chemistry. 281 (13): 8607–8612. doi:10.1074/jbc.M600274200. PMID 16446366.
14. Gao X, Wen J, Zhang L, Li X, Ning Y, Meng A, et al. (December 2008). "Dapper1 is a nucleocytoplasmic shuttling protein that negatively modulates Wnt signaling in the nucleus". The Journal of Biological Chemistry. 283 (51): 35679–35688. doi:10.1074/jbc.M804088200. PMID 18936100.
15. Chen H, Liu L, Ma B, Ma TM, Hou JJ, Xie GM, et al. (April 2011). "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. PMC 3083226. PMID 21262972.
16. Kivimäe S, Yang XY, Cheyette BN (June 2011). "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. PMC 3141656. PMID 21718540.
17. Saplakoglu Y (2021-03-24). "Meet the 'frodosome,' a brand new organelle". livescience.com. Retrieved 2021-12-01.
18. Yu C, Lang Y, Hou C, Yang E, Ren X, Li T (January 2022). "Distinctive Network Topology of Phase-Separated Proteins in Human Interactome". Journal of Molecular Biology. 434 (1): 167292. doi:10.1016/j.jmb.2021.167292. PMID 34624295. S2CID 238529546.
19. "OMIM Entry - # 617466 - TOWNES-BROCKS SYNDROME 2; TBS2". omim.org. Retrieved 2021-12-01.

• Genes on human chromosome 14
• Human proteins
• Human genes