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

More general terms

• HMG box transcription factor
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=6934
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:6934
• OMIM: https://mirror.omim.org/entry/125853
• OMIM: https://mirror.omim.org/entry/602228
• UniProt: http://www.uniprot.org/uniprot/Q9NQB0.html