This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pelletier, L. Articles by Manié, S. N. Search for Related Content PubMed PubMed Citation Articles by Pelletier, L. Articles by Manié, S. N.

-Secretase-Dependent Proteolysis of CD44 Promotes Neoplastic Transformation of Rat Fibroblastic Cells

¹ Génétique moléculaire, Signalisation et Cancer, UMR 5201, Faculté de Médecine, Lyon Cedex 08, France; ² The Austin Research Institute, Austin Health, Heidelberg, Victoria, Australia; ³ Laboratoire de Chimie des Protéines, ERM 201 INSERM/CEA/UJF, Grenoble Cedex 9, France; and ⁴ Société Génome Express, Meylan, France

Requests for reprints: Serge N. Manié, Génétique moléculaire, Signalisation et Cancer, UMR 5201, Faculte de Médecine, 8 Avenue Rockefeller, 69 373 Lyon Cedex 08, France. Phone: 33-4-78-77-72-72; Fax: 33-4-78-77-72-20; E-mail: manie{at}sante.univ-lyon1.fr.

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 -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 -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 -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. (Cancer Res 2006; 66(7): 3681-7)