TCF7L2

Transcription factor 7-like 2 (T-cell specific, HMG-box), also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene.[5][6] The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons and has autosomal dominant inheritance.[7][8] As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.[9]

TCF7L2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2GL7, 1JDH, 1JPW
Identifiers
Aliases	TCF7L2, TCF-4, TCF4, transcription factor 7 like 2
External IDs	OMIM: 602228 MGI: 1202879 HomoloGene: 7564 GeneCards: TCF7L2
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q25.2-q25.3 Start 112,950,247 bp[1] End 113,167,678 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 D2|19 51.59 cM Start 55,741,820 bp[2] End 55,933,654 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • sequence-specific DNA binding • DNA binding • beta-catenin binding • gamma-catenin binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • transcription factor binding • nuclear hormone receptor binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001948 protein binding • RNA polymerase II repressing transcription factor binding • armadillo repeat domain binding • protein kinase binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • chromatin binding Cellular component • beta-catenin-TCF7L2 complex • PML body • nucleoplasm • protein-DNA complex • nuclear chromatin • cell nucleus • transcription regulator complex Biological process • positive regulation of heparan sulfate proteoglycan biosynthetic process • positive regulation of protein kinase B signaling • regulation of transcription, DNA-templated • glucose homeostasis • regulation of transcription from RNA polymerase II promoter • response to glucose • Wnt signaling pathway • regulation of smooth muscle cell proliferation • negative regulation of sequence-specific DNA binding transcription factor activity • canonical Wnt signaling pathway involved in positive regulation of epithelial to mesenchymal transition • transcription, DNA-templated • positive regulation of protein export from nucleus • maintenance of DNA repeat elements • blood vessel development • myoblast fate commitment • cell cycle arrest • canonical Wnt signaling pathway • pancreas development • positive regulation of protein binding • regulation of hormone metabolic process • cellular proliferation • negative regulation of transcription, DNA-templated • fat cell differentiation • negative regulation of canonical Wnt signaling pathway • beta-catenin-TCF complex assembly • Wnt signaling pathway, calcium modulating pathway • positive regulation of insulin secretion • negative regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • negative regulation of type B pancreatic cell apoptotic process • negative regulation of extrinsic apoptotic signaling pathway • positive regulation of epithelial cell proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6934	21416
Ensembl	ENSG00000148737	ENSMUSG00000024985
UniProt	Q9NQB0	Q924A0
RefSeq (mRNA)	NM_001146274 NM_001146283 NM_001146284 NM_001146285 NM_001146286 NM_001198525 NM_001198526 NM_001198527 NM_001198528 NM_001198529 NM_001198530 NM_001198531 NM_030756 NM_001349870 NM_001349871 NM_001363501 NM_001367943	NM_001142918 NM_001142919 NM_001142920 NM_001142921 NM_001142922 NM_001142923 NM_001142924 NM_009333 NM_001331135 NM_001331136 NM_001331137 NM_001331138 NM_001331139 NM_001331140 NM_001331141 NM_001331142 NM_001331143 NM_001331144 NM_001331145 NM_001331146 NM_001331147 NM_001331148 NM_001331149 NM_001331150
RefSeq (protein)	NP_001139746 NP_001139755 NP_001139756 NP_001139757 NP_001139758 NP_001185454 NP_001185455 NP_001185456 NP_001185457 NP_001185458 NP_001185459 NP_001185460 NP_110383 NP_001336799 NP_001336800 NP_001350430 NP_001354872 NP_001139757.1	NP_001136390 NP_001136391 NP_001136392 NP_001136393 NP_001136394 NP_001136395 NP_001136396 NP_001318064 NP_001318065 NP_001318066 NP_001318067 NP_001318068 NP_001318069 NP_001318070 NP_001318071 NP_001318072 NP_001318073 NP_001318074 NP_001318075 NP_001318076 NP_001318077 NP_001318078 NP_001318079 NP_033359
Location (UCSC)	Chr 10: 112.95 – 113.17 Mb	Chr 19: 55.74 – 55.93 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Single-nucleotide polymorphisms (SNPs) in this gene are especially known to be linked to higher risk to develop type 2 diabetes,[9] gestational diabetes[10] and multiple other diseases.[11][12][13] The SNP rs7903146, within the TCF7L2 gene, is, to date, the most significant genetic marker associated with type 2 diabetes risk.[14]

Structure of complex between TCF7L2 (orange), β-catenin (red), and BCL9 (brown)[15]

Function

TCF7L2 is a transcription factor influencing the transcription of several genes thereby exerting a large variety of functions within the cell. It is a member of the TCF family that can form a bipartite transcription factor (β-catenin/TCF) alongside β-catenin.[9] Bipartite transcription factors can have large effects on the Wnt signalling pathway.[9] Stimulation of the Wnt signaling pathway leads to the association of β-catenin with BCL9, translocation to the nucleus, and association with TCF7L2,[16] which in turn results in the activation of Wnt target genes. The activation of the Wnt target genes specifically represses proglucagon synthesis in enteroendocrine cells.[9][8] The repression of TCF7L2 using HMG-box repressor (HBP1) inhibits Wnt signalling.[9] Therefore, TCF7L2 is an effector in the Wnt signalling pathway. TCF7L2's role in glucose metabolism is expressed in many tissues such as gut, brain, liver, and skeletal muscle. However, TCF7L2 does not directly regulate glucose metabolism in β-cells, but regulates glucose metabolism in pancreatic and liver tissues.[17]

The TCF7L2 gene encoding the TCF7L2 transcription factor, exhibits multiple functions through its polymorphisms and thus, is known as a pleiotropic gene. Type 2 diabetes T2DM susceptibility is exhibited in carriers of TCF7L2 rs7903146C>T[18][19] and rs290481T>C[19] polymorphisms.[18][19] TCF7L2 rs290481T>C polymorphism, however, has shown no significant correlation to the susceptibility to gestational diabetes mellitus (GDM) in a Chinese Han population, whereas the T alleles of rs7903146[19] and rs1799884[10] increase susceptibility to GDM in the Chinese Han population.[19][10] The difference in effects of the different polymorphisms of the gene indicate that the gene is indeed pleiotropic.

Structure

The TCF7L2 gene, encoding the TCF7L2 protein, is located on chromosome 10q25.2-q25.3. The gene contains 19 exons and has autosomal dominant inheritance.[7][8] Of the 19 exons, 5 are alternative.[8] The TCF7L2 protein contains 619 amino acids and its molecular mass is 67919 Da.[20] TCF7L2's secondary structure is a helix-turn-helix structure.[21]

Tissue distribution

TCF7L2 is primarily expressed in brain, liver, intestine and fat cells. It does not primarily operate in the β-cells in the pancreas.[22]

Clinical significance

Type 2 Diabetes

Several single nucleotide polymorphisms within the TCF7L2 gene have been associated with type 2 diabetes. Studies conducted by Ravindranath Duggirala and Michael Stern at The University of Texas Health Science Center at San Antonio were the first to identify strong linkage for type 2 diabetes at a region on Chromosome 10 in Mexican Americans [23] This signal was later refined by Struan Grant and colleagues at DeCODE genetics and isolated to the TCF7L2 gene.[24] The molecular and physiological mechanisms underlying the association of TCF7L2 with type 2 diabetes are under active investigation, but it is likely that TCF7L2 has important biological roles in multiple metabolic tissues, including the pancreas, liver and adipose tissue.[22][25] TCF7L2 polymorphisms can increase susceptibility to type 2 diabetes by decreasing the production of glucagon-like peptide-1 (GLP-1).[9]

Gestational Diabetes (GDM)

TCF7L2 modulates pancreatic islet β-cell function strongly implicating its significant association with GDM risk.[10] T alleles of rs7903146[19] and rs1799884[10] TCF7L2 polymorphisms increase susceptibility to GDM in the Chinese Han population.[19][10]

Cancer

TCF7L2 plays a role in colorectal cancer.[11] A frameshift mutation of TCF7L2 provided evidence that TCF7L2 is implicated in colorectal cancer.[26][27] The silencing of TCF7L2 in KM12 colorectal cancer cells provided evidence that TCF7L2 played a role in proliferation and metastasis of cancer cells in colorectal cancer.[11]

Variants of the gene are most likely involved in many other cancer types.[28] TCF7L2 is indirectly involved in prostate cancer through its role in activating the PI3K/Akt pathway, a pathway involved in prostate cancer.[29]

Schizophrenia

Single nucleotide polymorphisms (SNPs) in TCF7L2 gene have shown an increase in susceptibility to schizophrenia in Arab, European and Chinese Han populations. In the Chinese Han population, SNP rs12573128[12] in TCF7L2 is the variant that was associated with an increase in schizophrenia risk. This marker is used as a pre-diagnostic marker for schizophrenia.[12]

Multiple sclerosis

TCF7L2 is downstream of the WNT/β-catenin pathways. The activation of the WNT/β-catenin pathways have been associated demyelination in multiple sclerosis.[13] TCF7L2 is unregulated during early remyelination, leading scientists to believe that it is involved in remyelination.[13] TCF7L2 could act in dependence or independent of the WNT/β-catenin pathways.[13]

Model organisms

Model organisms have been used in the study of TCF7L2 function. A conditional knockout mouse line called Tcf7l2^{tm1a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.[30] Male and female animals underwent a standardized phenotypic screen[31] to determine the effects of deletion.[32][33][34][35] Additional screens performed: - In-depth immunological phenotyping[36]

Variations of the protein encoding gene are found in rats, zebra fish, drosophila, and budding yeast.[37] Therefore, all of those organisms can be used as model organisms in the study of TCF7L2 function.

Nomenclature

TCF7L2 is the symbol officially approved by the HUGO Gene Nomenclature Committee for the transcription factor 4 gene (TCF4).

See also

• TCF/LEF family

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000024985 - Ensembl, May 2017
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5. "Entrez Gene: TCF7L2".
6. Castrop J, van Norren K, Clevers H (February 1992). "A gene family of HMG-box transcription factors with homology to TCF-1". Nucleic Acids Research. 20 (3): 611. doi:10.1093/nar/20.3.611. PMC 310434. PMID 1741298.
7. "TCF7L2 transcription factor 7 like 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-30.
8. Online Mendelian Inheritance in Man (OMIM): TRANSCRIPTION FACTOR 7-LIKE 2;TCF7L2 - 602228{
9. 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.
10. Zhang C, Bao W, Rong Y, Yang H, Bowers K, Yeung E, Kiely M (2013-05-19). "Genetic variants and the risk of gestational diabetes mellitus: a systematic review". Human Reproduction Update. 19 (4): 376–90. doi:10.1093/humupd/dmt013. PMC 3682671. PMID 23690305.
11. Torres S, García-Palmero I, Marín-Vicente C, Bartolomé RA, Calviño E, Fernández-Aceñero MJ, Casal JI (November 2017). "Proteomic Characterization of Transcription and Splicing Factors Associated with a Metastatic Phenotype in Colorectal Cancer" (PDF). Journal of Proteome Research. 17 (1): 252–264. doi:10.1021/acs.jproteome.7b00548. hdl:10261/160082. PMID 29131639.
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13. Vallée A, Vallée JN, Guillevin R, Lecarpentier Y (September 2017). "Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis". Cellular and Molecular Neurobiology. 38 (4): 783–795. doi:10.1007/s10571-017-0550-9. PMID 28905149. S2CID 4620853.
14. Vaquero AR, Ferreira NE, Omae SV, Rodrigues MV, Teixeira SK, Krieger JE, Pereira AC (October 2012). "Using gene-network landscape to dissect genotype effects of TCF7L2 genetic variant on diabetes and cardiovascular risk". Physiological Genomics. 44 (19): 903–14. doi:10.1152/physiolgenomics.00030.2012. PMID 22872755.
15. PDB: 2GL7​; Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W (October 2006). "Crystal structure of a beta-catenin/BCL9/Tcf4 complex". Molecular Cell. 24 (2): 293–300. doi:10.1016/j.molcel.2006.09.001. PMID 17052462.
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17. Facchinello N, Tarifeño-Saldivia E, Grisan E, Schiavone M, Peron M, Mongera A, Ek O, Schmitner N, Meyer D, Peers B, Tiso N, Argenton F (August 2017). "Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration". Scientific Reports. 7 (1): 9605. Bibcode:2017NatSR...7.9605F. doi:10.1038/s41598-017-09867-x. PMC 5575064. PMID 28851992.
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19. Zhu L, Xie Z, Lu J, Hao Q, Kang M, Chen S, Tang W, Ding H, Chen Y, Liu C, Wu H (September 2017). "TCF7L2 rs290481 T>C polymorphism is associated with an increased risk of type 2 diabetes mellitus and fasting plasma glucose level". Oncotarget. 8 (44): 77000–77008. doi:10.18632/oncotarget.20300. PMC 5652758. PMID 29100364.
20. Database, GeneCards Human Gene. "TCF7L2 Gene - GeneCards | TF7L2 Protein | TF7L2 Antibody". www.genecards.org. Retrieved 2017-11-30.
21. "TCF7L2 - Transcription factor 7-like 2 - Homo sapiens (Human) - TCF7L2 gene & protein". www.uniprot.org. Retrieved 2017-11-30.
22. Nobrega MA (March 2013). "TCF7L2 and glucose metabolism: time to look beyond the pancreas". Diabetes. 62 (3): 706–8. doi:10.2337/db12-1418. PMC 3581232. PMID 23431017.
23. Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O'Connell P, Stern MP (April 1999). "Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans". American Journal of Human Genetics. 64 (4): 1127–40. doi:10.1086/302316. PMC 1377837. PMID 10090898.
24. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (March 2006). "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes". Nature Genetics. 38 (3): 320–3. doi:10.1038/ng1732. PMID 16415884. S2CID 28825825.
25. Jin T (June 2016). "Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis". Endocrine Reviews. 37 (3): 254–77. doi:10.1210/er.2015-1146. PMID 27159876.
26. Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD (April 2008). "Transcription factor 7-like 2 polymorphism and colon cancer". Cancer Epidemiology, Biomarkers & Prevention. 17 (4): 978–82. doi:10.1158/1055-9965.EPI-07-2687. PMC 2587179. PMID 18398040.
27. Hazra A, Fuchs CS, Chan AT, Giovannucci EL, Hunter DJ (November 2008). "Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk". Cancer Causes & Control. 19 (9): 975–80. doi:10.1007/s10552-008-9164-3. PMC 2719293. PMID 18478343.
28. Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L (July 2008). "A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer". Proceedings of the National Academy of Sciences of the United States of America. 105 (28): 9697–702. Bibcode:2008PNAS..105.9697T. doi:10.1073/pnas.0804709105. PMC 2453074. PMID 18621708.
29. Sun P, Xiong H, Kim TH, Ren B, Zhang Z (February 2006). "Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells". Molecular Pharmacology. 69 (2): 520–31. doi:10.1124/mol.105.019620. PMID 16291872. S2CID 10148857.
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Further reading

• Segditsas S, Tomlinson I (December 2006). "Colorectal cancer and genetic alterations in the Wnt pathway". Oncogene. 25 (57): 7531–7. doi:10.1038/sj.onc.1210059. PMID 17143297.
• Florez JC (July 2007). "The new type 2 diabetes gene TCF7L2". Current Opinion in Clinical Nutrition and Metabolic Care. 10 (4): 391–6. doi:10.1097/MCO.0b013e3281e2c9be. PMID 17563454. S2CID 21362394.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H (March 1997). "Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma". Science. 275 (5307): 1784–7. doi:10.1126/science.275.5307.1784. hdl:20.500.11755/27e2349d-dfbe-4458-9a4e-3fa15f0d2420. PMID 9065401. S2CID 33935423.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (September 1998). "Identification of c-MYC as a target of the APC pathway". Science. 281 (5382): 1509–12. Bibcode:1998Sci...281.1509H. doi:10.1126/science.281.5382.1509. PMID 9727977.
• Barker N, Huls G, Korinek V, Clevers H (January 1999). "Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium". The American Journal of Pathology. 154 (1): 29–35. doi:10.1016/S0002-9440(10)65247-9. PMC 1853446. PMID 9916915.
• Omer CA, Miller PJ, Diehl RE, Kral AM (March 1999). "Identification of Tcf4 residues involved in high-affinity beta-catenin binding". Biochemical and Biophysical Research Communications. 256 (3): 584–90. doi:10.1006/bbrc.1999.0379. PMID 10080941.
• Giannini AL, Vivanco MM, Kypta RM (March 2000). "Analysis of beta-catenin aggregation and localization using GFP fusion proteins: nuclear import of alpha-catenin by the beta-catenin/Tcf complex". Experimental Cell Research. 255 (2): 207–20. doi:10.1006/excr.1999.4785. PMID 10694436.
• Duval A, Busson-Leconiat M, Berger R, Hamelin R (2000). "Assignment of the TCF-4 gene (TCF7L2) to human chromosome band 10q25.3". Cytogenetics and Cell Genetics. 88 (3–4): 264–5. doi:10.1159/000015534. PMID 10828605. S2CID 13148464.
• Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R (July 2000). "The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines". Cancer Research. 60 (14): 3872–9. PMID 10919662.
• Brantjes H, Roose J, van De Wetering M, Clevers H (April 2001). "All Tcf HMG box transcription factors interact with Groucho-related co-repressors". Nucleic Acids Research. 29 (7): 1410–9. doi:10.1093/nar/29.7.1410. PMC 31284. PMID 11266540.
• Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B (October 2001). "Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion". The Journal of Biological Chemistry. 276 (42): 38563–9. doi:10.1074/jbc.M105376200. PMID 11504726.
• Miravet S, Piedra J, Miró F, Itarte E, García de Herreros A, Duñach M (January 2002). "The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin". The Journal of Biological Chemistry. 277 (3): 1884–91. doi:10.1074/jbc.M110248200. PMID 11711551.
• Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W (December 2001). "Tcf4 can specifically recognize beta-catenin using alternative conformations". Nature Structural Biology. 8 (12): 1048–52. doi:10.1038/nsb718. PMID 11713475. S2CID 33878077.
• Poy F, Lepourcelet M, Shivdasani RA, Eck MJ (December 2001). "Structure of a human Tcf4-beta-catenin complex". Nature Structural Biology. 8 (12): 1053–7. doi:10.1038/nsb720. PMID 11713476. S2CID 24798619.
• Thiele A, Wasner M, Müller C, Engeland K, Hauschildt S (December 2001). "Regulation and possible function of beta-catenin in human monocytes". Journal of Immunology. 167 (12): 6786–93. doi:10.4049/jimmunol.167.12.6786. PMID 11739494.
• Marchenko GN, Marchenko ND, Leng J, Strongin AY (April 2002). "Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin". The Biochemical Journal. 363 (Pt 2): 253–62. doi:10.1042/0264-6021:3630253. PMC 1222473. PMID 11931652.
• Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER (June 2002). "Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling". The Journal of Biological Chemistry. 277 (24): 21657–65. doi:10.1074/jbc.M200139200. PMID 11940574.

External links

• TCF7L2 here called TCF4 features on this Wnt pathway web site: Wnt signalling molecules TCFs
• Structure determination of TCF7L2: PDB entry 2GL7 and related publication on PubMed
• PubMed GeneRIFs (summaries of related scientific publications) -
• Weizmann Institute GeneCard for TCF7L2
• Overview of all the structural information available in the PDB for UniProt: Q9NQB0 (Transcription factor 7-like 2) at the PDBe-KB.