1. Critical interactions between TGF-beta signaling/ELF, and E-cadherin/beta-catenin mediated tumor suppression.
- Author
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Katuri V, Tang Y, Li C, Jogunoori W, Deng CX, Rashid A, Sidawy AN, Evans S, Reddy EP, Mishra B, and Mishra L
- Subjects
- Animals, Cadherins physiology, Carrier Proteins physiology, Cell Adhesion, Epithelial Cells physiology, Gastrointestinal Neoplasms physiopathology, Gene Expression Profiling, Mice, Microfilament Proteins physiology, Signal Transduction, Smad4 Protein biosynthesis, Smad4 Protein genetics, beta Catenin physiology, Carrier Proteins biosynthesis, DNA-Binding Proteins, Gastrointestinal Neoplasms genetics, Microfilament Proteins biosynthesis, Transforming Growth Factor beta physiology
- Abstract
Inactivation of the transforming growth factor-beta (TGF-beta) 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 beta-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-beta-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-beta 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-beta signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.
- Published
- 2006
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