Gamma-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 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.
Génétique moléculaire, Signalisation et Cancer, UMR 5201, Faculté de Médecine, 8 Avenue Rockefeller, 69-373 Lyon Cedex 08, France.
Ludivine
L
Pelletier
Patricia
P
Guillaumot
Barbara
B
Frêche
Céline
C
Luquain
Dale
D
Christiansen
Sabine
S
Brugière
Jérome
J
Garin
Serge N
SN
Manié
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D015854:Up-Regulation
D003902:Detergents; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human