γ-Secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-04, Vol.66 (7), p.3681-3687
• Main Authors: PELLETIER, Ludivine, GUILLAUMOT, Patricia, FRECHE, Barbara, LUQUAIN, Céline, CHRISTIANSEN, Dale, BRUGIERE, Sabine, GARIN, Jérome, MANIC, Serge N
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amyloid Precursor Protein Secretases; Animals; Antineoplastic agents; Aspartic Acid Endopeptidases; Biochemistry, Molecular Biology; Biological and medical sciences; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Detergents - pharmacology; Endopeptidases - metabolism; Fibroblasts - enzymology; Fibroblasts - metabolism; Fibroblasts - pathology; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Life Sciences; Medical sciences; Molecular Sequence Data; Mutagenesis, Site-Directed; Pharmacology. Drug treatments; Protein Isoforms; Protein Structure, Tertiary; Rats; Tumors; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3870

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.