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transcription factor 7-like 2; HMG box transcription factor 4; T-cell-specific transcription factor 4; T-cell factor 4; TCF-4; hTCF-4 (TCF7L2 TCF4)

Function: - participates in Wnt signaling pathway - modulates myc expression - repressor in the absence of CTNNB1 & activator in its presence - with CTNNB1, activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' - maintenance of epithelial stem-cells in small intestine - TLE1, TLE2, TLE3 & TLE4 repress transactivation mediated by TCF7L2/TCF4 & CTNNB1 - expression of dominant-negative mutants results in cell-cycle arrest in G1 - necessary for the maintenance of the epithelial stem-cell compartment of the small intestine - in vitro, phosphorylated by TNIK - phosphorylated at Thr-201 &/or Thr-212 by NLK - phosphorylation by NLK at these sites inhibits DNA-binding by TCF7L2/TCF4, thus preventing transcriptional activation of target genes of the canonical Wnt/beta-catenin signaling pathway - polysumoylated - sumoylation is enhanced by PIAS family members - desumoylation is enhanced by SENP2 - sumoylation/desumoylation regulates TCF7L2/TCF4 transcription activity in the Wnt/beta-catenin signaling pathway without altering interaction with CTNNB1 nor binding to DNA - interacts with TGFB1I1 (putative) - interacts with CTNNB1 (via the armadillo repeat) - forms stable transcription complex - interacts with EP300 - interacts with NLK - interacts with CCDC85B (probably through the HMG box) - prevents interaction with CTNNB1 - interacts with TNIK - interacts with MAD2L2 - prevents TCF7L2/TCF4 binding to promZIPK/DAPK3oters, negatively modulating its transcriptional activity - interacts with ZIPK/DAPK3 - interacts with XIAP/BIRC4 & TLE3 Structure: - the promoter-specific activation domain interacts with the transcriptional coactivator EP300 - belongs to the TCF/LEF family - contains 1 HMG box DNA-binding domain Compartment: - nucleus, PML body - diffuse pattern colocalizes with SUMO1 & PIAS4 in a subset of PML nuclear bodies Alternative splicing: named isoforms=10 Expression: - detected in epithelium from small intestine - highest expression at the top of the crypts - gradient of expression from crypt to villus - highly expressed in crypt regions & barely detectable in villi in epithelium from fetal small intestine at week 16 - at week 22 expression in villi had increased strongly - detected in colon epithelium & colon cancer - detected in epithelium from mammary gland & breast carcinomas Pathology: - constitutive activation & subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling & longevity) in cells that should normally undergo terminal differentiation & constitute the primary transforming event in colorectal cancer (CRC) - genetic variations in TCF7L2 are associated with susceptibility to non-insulin-dependent diabetes mellitus - rs7903146 polymorphism associated with increased risk of stroke

General

HMG box transcription factor phosphoprotein

Properties

SIZE: entity length = 619 aa MW = 68 kD COMPARTMENT: cell nucleus MOTIF: binding site SITE: 1-53 FOR-BINDING-OF: beta catenin proline-rich region SITE: 178-317 MOTIF: proline residue (SEVERAL) Mediates interaction with MAD2L2 {201-395} MOTIF: Thr phosphorylation site {T201} Thr phosphorylation site {T212} HMG box SITE: 350-418 nuclear translocation signal {425-430} Promoter-specific activation {459-505}

Database Correlations

OMIM correlations MORBIDMAP 602228 UniProt Q9NQB0 PFAM correlations Entrez Gene 6934 Kegg hsa:6934

References

  1. UniProt :accession Q9NQB02
  2. Corella D et al Mediterranean Diet Reduces the Adverse Effect of the TCF7L2- rs7903146 Polymorphism on Cardiovascular Risk Factors and Stroke Incidence. A randomized controlled trial in a high- cardiovascular-risk population. PMID: 23942586 http://care.diabetesjournals.org/content/early/2013/08/06/dc13-0955.abstract