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

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 signal...

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Bibliographic Details
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
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-3870