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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 25 Issue 13 Pg. 1871-86 (Mar 23 2006) ISSN: 0950-9232 [Print] England
• PMID: 16288220 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Carrier Proteins
• DNA-Binding Proteins
• Microfilament Proteins
• Smad4 Protein
• Smad4 protein, mouse
• Transforming Growth Factor beta
• beta Catenin
• fodrin

Topics

• Animals
• Cadherins (physiology)
• Carrier Proteins (biosynthesis, physiology)
• Cell Adhesion
• DNA-Binding Proteins
• Epithelial Cells (physiology)
• Gastrointestinal Neoplasms (genetics, physiopathology)
• Gene Expression Profiling
• Mice
• Microfilament Proteins (biosynthesis, physiology)
• Signal Transduction
• Smad4 Protein (biosynthesis, genetics)
• Transforming Growth Factor beta (physiology)
• beta Catenin (physiology)