Critical interactions between TGF-β signaling/ELF, and E-cadherin/β-catenin mediated tumor suppression

V. Katuri, Y. Tang, C. Li, W. Jogunoori, C. X. Deng, A. Rashid, A. N. Sidawy, S. Evans, E. P. Reddy, B. Mishra, L. Mishra

Research output: Contribution to journalArticlepeer-review

Abstract

Inactivation of the transforming growth factor-β (TGF-β) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/- and elf+/-/Smad4+/- mutant mice. We found that embryonic liver fodrin (ELF), a β-Spectrin originally identified in endodermal stem/ progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-β-catenin-dependent epithelial cell-cell adhesion is disrupted in elf+/- Smad4 +/- mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-β stimulation. In contrast, elf+/- /Smad4+/- mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-β signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.

Original languageEnglish (US)
Pages (from-to)1871-1886
Number of pages16
JournalOncogene
Volume25
Issue number13
DOIs
StatePublished - Mar 23 2006

Keywords

  • E-cadherin
  • ELF
  • Gastrointestinal cancer
  • Smad4
  • Spectrin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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