TCF/LEF family

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Composite gene models of TCF/LEF genes. Extracted from Torres-Aguila et. al. (2022). TCFLEF gene models.tif
Composite gene models of TCF/LEF genes. Extracted from Torres-Aguila et. al. (2022).

The TCF/LEF family (T cell factor/lymphoid enhancer factor family) is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic [2] and stem-cell development, [3] but also had been found to play a role in cancer [4] and diabetes. [5] TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors. [6]

Contents

History

The discovery of the TCF/LEF genes as nuclear Wnt pathway components in the 90s [7] [8] was a pivotal breakthrough for the Wnt signalling research field, plugging an important knowledge gap and enabling subsequent understanding of transcriptional regulation of Wnt target genes, particularly in embryonic development and cancer.

Before this discovery it was only known that upstream Wnt signalling mechanisms regulated the cytoplasmic abundance of the beta-catenin protein, which as a consequence translocated into the cell nucleus. However, since the protein structure of beta-catenin did not reveal any DNA-binding domain, it was still unclear how nuclear beta-catenin could regulate Wnt target genes. Following the discovery, a model was established whereby Wnt signalling-regulated beta-catenin in the nucleus attaches to TCF/LEF DNA binding proteins, which recognise the DNA consensus sequence around the core 'CTTTG', called Wnt Response Element (WRE). [9]

This rule that beta-catenin-TCF interaction on DNA regulates Wnt target gene expression, has nonetheless been broken by examples of Wnt- and beta-catenin-independent functions for TCF/LEF proteins (for instance in zebrafish CNS development [10] ) and functional association of Wnt-regulated beta-catenin with other DNA-binding transcription factors such as SOX, [11] FOXO, [12] TBX. [13] Then again, this beta-catenin-TCF interaction on DNA is now revealed as but the core of much larger protein complexes regulating transcription, called the Wnt enhanceosomes. [14] Conversely, additional mechanisms regulating TCF/LEF protein function have been discovered, such as phosphorylation [15] and sumoylation. [16]

Structure

The structure and function of TCF/LEF proteins explains this bimodal function. TCF/LEF genes encode proteins with an elaborate structure that can however be summarised by considering four main domains:

  1. N-terminal domain: mediating interaction with beta-catenin, which is highly conserved and mediates the transcriptional activator function.
  2. Control region: includes sequences regulating and mediating the transcriptional repressor function and encoding a transcriptional repressor binding domain for the Groucho family.
  3. DNA-binding domain: includes a very highly conserved HMG (High Mobility Group) DNA-binding domain and the NLS (nuclear localisation sequence).
  4. C-terminal tail: may contain an additional DNA-binding domain and an additional transcriptional repressor binding domain. [17]

Diversity in TCF/LEF protein structure and function comes from having different genes. Humans and jawed vertebrates generally have four genes encoding TCF/LEF proteins:

Further diversity comes from expression from the same gene of alternative transcripts encoding different protein isoforms, particularly from the TCF7 and TCF7L2 genes:

Function

TCF/LEF proteins function as bimodal transcription factors:

Thus, as a consequence, Wnt target genes are actively repressed in the absence of Wnt signalling activity, then activated when Wnt signalling actively drives beta-catenin into the nucleus. [23]

TCF/LEF genes support diverse functions in embryonic development, stem cell biology, and in disease. [24] [25] Given the conservation of structure, functions of different TCF/LEF genes and proteins are often redundant in many organs and tissues where Wnt signalling is important, yet genetic analysis suggested from the beginning that this redundancy is only partial, suggesting TCF/LEF gene- and TCF isoform-specific functions, many of which are only now beginning to be discovered.

Prominent functions of TCF/LEF genes in embryonic development include vertebrate dorsal axis induction, anterior-posterior patterning of the developing Central Nervous System, neural crest development and many functions in organ development. Prominent functions of TCF/LEF genes in stem cell development have been particularly well dissected during the hair follicle cycle. [26] [27] TCF/LEF genes have roles in many cancers, with their role in colorectal cancer possibly being the best understood. [28] However, other human diseases have also been linked to TCF/LEF genes, particularly type 2 diabetes. [29] [30]

Related Research Articles

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<span class="mw-page-title-main">TCF7L2</span> Protein-coding gene in humans

Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.

<span class="mw-page-title-main">AXIN1</span> Protein-coding gene in the species Homo sapiens

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

<span class="mw-page-title-main">Lymphoid enhancer-binding factor 1</span> Protein-coding gene in the species Homo sapiens

Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.

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<span class="mw-page-title-main">WNT3A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">BCL9</span> Protein-coding gene in the species Homo sapiens

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Reptin is a tumor repressor protein that is a member of the ATPases Associated with various cellular Activities (AAA+) helicase family and regulates KAI1. Desumoylation of reptin alters the repressive function of reptin and its association with HDAC1. The sumoylation status of reptin modulates the invasive activity of cancer cells with metastatic potential. Reptin was reported in 2010 to be a good marker for metastasis. Another name for reptin, RuvB-like 2 comes from its similarity to RuvB, an ATP-dependent helicase found in bacteria. Reptin is highly conserved, being found in yeast, drosophila, and humans. It presents itself as a member of a number of different protein complexes, most of which function in chromatin modification, including PRC1, TIP60/NuA4 and INO80. Hence, it also has the names INO80J, TIP48, and TIP49B. In the majority of its functions, reptin is paired with a very similar protein, pontin (RUVBL1).

<span class="mw-page-title-main">TCF7L1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Dishevelled binding antagonist of beta catenin 1</span> Developmental protein

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References

  1. ↑ Torres‐Aguila, Nuria P.; Salonna, Marika; Hoppler, Stefan; Ferrier, David E. K. (2022-02-03). "Evolutionary diversification of the canonical Wnt signaling effector TCF/LEF in chordates". Development, Growth & Differentiation. 64 (3): 120–137. doi:10.1111/dgd.12771. hdl: 2164/18617 . ISSN   0012-1592. PMC   9303524 . PMID   35048372. S2CID   246161317.
  2. ↑ Logan, Catriona Y.; Nusse, Roel (November 2004). "The WNT Signaling Pathway in Development and Disease". Annual Review of Cell and Developmental Biology. 20 (1): 781–810. doi:10.1146/annurev.cellbio.20.010403.113126. PMID   15473860.
  3. ↑ Nusse, R (May 2008). "Wnt signaling and stem cell control". Cell Research. 18 (5): 523–7. doi: 10.1038/cr.2008.47 . PMID   18392048. S2CID   2503910.
  4. ↑ Zhan, T; Rindtorff, N; Boutros, M (March 2017). "Wnt signaling in cancer". Oncogene. 36 (11): 1461–1473. doi:10.1038/onc.2016.304. PMC   5357762 . PMID   27617575.
  5. ↑ Laudes, M (April 2011). "Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes". Journal of Molecular Endocrinology. 46 (2): R65-72. doi: 10.1530/JME-10-0169 . PMID   21247979.
  6. ↑ Brantjes H, Barker N, van Es J, Clevers H (February 2002). "TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling". Biol. Chem. 383 (2): 255–61. doi:10.1515/BC.2002.027. PMID   11934263. S2CID   25665021.
  7. ↑ Behrens, J; von Kries, JP; Kühl, M; Bruhn, L; Wedlich, D; Grosschedl, R; Birchmeier, W (15 August 1996). "Functional interaction of beta-catenin with the transcription factor LEF-1". Nature. 382 (6592): 638–42. Bibcode:1996Natur.382..638B. doi:10.1038/382638a0. PMID   8757136. S2CID   4369341.
  8. ↑ Huber, O; Korn, R; McLaughlin, J; Ohsugi, M; Herrmann, BG; Kemler, R (September 1996). "Nuclear localization of beta-catenin by interaction with transcription factor LEF-1". Mechanisms of Development. 59 (1): 3–10. doi: 10.1016/0925-4773(96)00597-7 . PMID   8892228. S2CID   14324471.
  9. ↑ Cadigan, KM; Waterman, ML (1 November 2012). "TCF/LEFs and Wnt signaling in the nucleus". Cold Spring Harbor Perspectives in Biology. 4 (11): a007906. doi:10.1101/cshperspect.a007906. PMC   3536346 . PMID   23024173.
  10. ↑ Duncan, RN; Panahi, S; Piotrowski, T; Dorsky, RI (2015). "Identification of Wnt Genes Expressed in Neural Progenitor Zones during Zebrafish Brain Development". PLOS ONE. 10 (12): e0145810. Bibcode:2015PLoSO..1045810D. doi: 10.1371/journal.pone.0145810 . PMC   4699909 . PMID   26713625.
  11. ↑ Kormish, JD; Sinner, D; Zorn, AM (January 2010). "Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease". Developmental Dynamics. 239 (1): 56–68. doi:10.1002/dvdy.22046. PMC   3269784 . PMID   19655378.
  12. ↑ Essers, MA; de Vries-Smits, LM; Barker, N; Polderman, PE; Burgering, BM; Korswagen, HC (20 May 2005). "Functional interaction between beta-catenin and FOXO in oxidative stress signaling". Science. 308 (5725): 1181–4. Bibcode:2005Sci...308.1181E. doi:10.1126/science.1109083. PMID   15905404. S2CID   24572861.
  13. ↑ Zimmerli, Dario; Borrelli, Costanza; Jauregi-Miguel, Amaia; Söderholm, Simon; Brütsch, Salome; Doumpas, Nikolaos; Reichmuth, Jan; Murphy-Seiler, Fabienne; Aguet, MIchel; Basler, Konrad; Moor, Andreas E; Cantù, Claudio (18 August 2020). "TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex". eLife. 9. doi: 10.7554/eLife.58123 . PMC   7434441 . PMID   32808927.
  14. ↑ Gammons, M; Bienz, M (April 2018). "Multiprotein complexes governing Wnt signal transduction". Current Opinion in Cell Biology. 51: 42–49. doi:10.1016/j.ceb.2017.10.008. PMID   29153704.
  15. ↑ Sokol, SY (July 2011). "Wnt signaling through T-cell factor phosphorylation". Cell Research. 21 (7): 1002–12. doi:10.1038/cr.2011.86. PMC   3193496 . PMID   21606952.
  16. ↑ Yamamoto, H; Ihara, M; Matsuura, Y; Kikuchi, A (1 May 2003). "Sumoylation is involved in beta-catenin-dependent activation of Tcf-4". The EMBO Journal. 22 (9): 2047–59. doi:10.1093/emboj/cdg204. PMC   156076 . PMID   12727872.
  17. ↑ Hoppler, Stefan; Waterman, Marian L. (2014). "Evolutionary Diversification of Vertebrate TCF/LEF Structure, Function, and Regulation". WNT Signaling in Development and Disease: 225–237. doi:10.1002/9781118444122.ch17. ISBN   9781118444122.
  18. ↑ Van de Wetering, M; Castrop, J; Korinek, V; Clevers, H (March 1996). "Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties". Molecular and Cellular Biology. 16 (3): 745–52. doi:10.1128/MCB.16.3.745. PMC   231054 . PMID   8622675.
  19. ↑ Hovanes, K; Li, TW; Munguia, JE; Truong, T; Milovanovic, T; Lawrence Marsh, J; Holcombe, RF; Waterman, ML (May 2001). "Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer". Nature Genetics. 28 (1): 53–7. doi:10.1038/ng0501-53. PMID   11326276. S2CID   28974522.
  20. ↑ Liu, F; van den Broek, O; Destrée, O; Hoppler, S (December 2005). "Distinct roles for Xenopus Tcf/Lef genes in mediating specific responses to Wnt/beta-catenin signalling in mesoderm development". Development. 132 (24): 5375–85. doi: 10.1242/dev.02152 . PMID   16291789. S2CID   20515922.
  21. ↑ Atcha, FA; Syed, A; Wu, B; Hoverter, NP; Yokoyama, NN; Ting, JH; Munguia, JE; Mangalam, HJ; Marsh, JL; Waterman, ML (December 2007). "A unique DNA binding domain converts T-cell factors into strong Wnt effectors". Molecular and Cellular Biology. 27 (23): 8352–63. doi:10.1128/MCB.02132-06. PMC   2169181 . PMID   17893322.
  22. ↑ Ravindranath, AJ; Cadigan, KM (3 August 2016). "The Role of the C-Clamp in Wnt-Related Colorectal Cancers". Cancers. 8 (8): 74. doi: 10.3390/cancers8080074 . PMC   4999783 . PMID   27527215.
  23. ↑ Ramakrishnan, AB; Cadigan, KM (2017). "Wnt target genes and where to find them". F1000Research. 6: 746. doi: 10.12688/f1000research.11034.1 . PMC   5464219 . PMID   28649368.
  24. ↑ Hoppler, S; Kavanagh, CL (1 February 2007). "Wnt signalling: variety at the core". Journal of Cell Science. 120 (Pt 3): 385–93. doi: 10.1242/jcs.03363 . PMID   17251379. S2CID   30976795.
  25. ↑ Hoppler, Stefan; Moon, Randall T. (2014). Wnt signaling in development and disease : molecular mechanisms and biological functions. Hoboken, New Jersey. ISBN   9781118444122.{{cite book}}: CS1 maint: location missing publisher (link)
  26. ↑ DasGupta, R; Fuchs, E (October 1999). "Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation". Development. 126 (20): 4557–68. doi:10.1242/dev.126.20.4557. PMID   10498690.
  27. ↑ Merrill, BJ; Gat, U; DasGupta, R; Fuchs, E (1 July 2001). "Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin". Genes & Development. 15 (13): 1688–705. doi:10.1101/gad.891401. PMC   312726 . PMID   11445543.
  28. ↑ Mayer, Claus-Dieter; Magon de La Giclais, Soizick; Alsehly, Fozan; Hoppler, Stefan (May 2020). "Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies". Genes. 11 (5): 538. doi: 10.3390/genes11050538 . PMC   7288467 . PMID   32403323.
  29. ↑ Jin, T; Liu, L (November 2008). "The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus". Molecular Endocrinology. 22 (11): 2383–92. doi: 10.1210/me.2008-0135 . PMID   18599616.
  30. ↑ Chen, X; Ayala, I; Shannon, C; Fourcaudot, M; Acharya, NK; Jenkinson, CP; Heikkinen, S; Norton, L (April 2018). "The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function". Diabetes. 67 (4): 554–568. doi:10.2337/db17-0318. PMC   5860863 . PMID   29317436.
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