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

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.