Publications & Reports

Gamma-secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells.

Pelletier L, Guillaumot P, Freche B, Luquain C, Christiansen D, Brugiere S, Garin J, Manie SN
Genetique moleculaire, Signalisation et Cancer, UMR 5201, Faculte de Medecine, 8 Avenue Rockefeller, 69-373 Lyon Cedex 08, France.

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.

Publication

  • Journal: Cancer Research
  • Published: 01/04/2006
  • Volume: 66
  • Issue: 7
  • Pagination: 3681-3687