Gamma-secretase-dependent Proteolysis of Cd44 Promotes Neoplastic Transformation of Rat Fibroblastic Cells.
From: Génétique moléculaire, Signalisation et Cancer, UMR 5201, Faculté de Médecine, 8 Avenue Rockefeller, 69-373 Lyon Cedex 08, France.
Cancer research
- Publish Date: Apr 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 7
- Pages: 3681-7
- Medium: Print
- Language: English
- Citation (JAMA): Pelletier Ludivine, Guillaumot Patricia, Frêche Barbara, et al. Gamma-secretase-dependent Proteolysis of Cd44 Promotes Neoplastic Transformation of Rat Fibroblastic Cells.. Cancer Res. Apr 2006;66:3681-7
Abstract
The metalloprotease-dependent extracellular domain cleavage of the adhesion molecule CD44 is frequently observed in human tumors and is thought to promote metastasis. This cleavage is followed by gamma-secretase-dependent release of CD44 intracellular domain (CD44-ICD), which exhibits nuclear signaling activity. Using a reversible Ret-dependent oncogenic conversion model and a restricted proteomic approach, we identified a positive correlation between the neoplastic transformation of Rat-1 cells and the expression of standard CD44. In these transformed cells, CD44 was found to undergo a sequential metalloprotease and gamma-secretase cleavage, resulting in an increase in expression of CD44-ICD. We showed that this proteolytic fragment possesses a transforming activity. In support of this role, a significant and specific reduction in Ret-induced transformation of Rat-1 cells was observed following drug-mediated inhibition of gamma-secretase. Taken together, these findings suggest that the shedding of CD44 may not only modulate metastasis but also affects earlier events in tumorigenesis through the release of CD44-ICD.
Mesh Headings (Keywords): Amino Acid Sequence, Amyloid Precursor Protein Secretases, Animals, Antigens, CD44, Aspartic Endopeptidases, Cell Membrane, Cell Transformation, Neoplastic, Detergents, Endopeptidases, Fibroblasts, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Isoforms, Protein Structure, Tertiary, Rats, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 16585194
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