LRP-1--CD44, a new cell surface complex regulating tumor cell adhesion.
Fiche publication
Date publication
août 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DEDIEU Stéphane, Dr DEVY Jérôme, Dr LANGLOIS Benoît, Pr MARTINY Laurent
Tous les auteurs :
Perrot G, Langlois B, Devy J, Jeanne A, Verzeaux L, Almagro S, Sartelet H, Hachet C, Schneider C, Sick E, David M, Khrestchatisky M, Emonard H, Martiny L, Dedieu S
Lien Pubmed
Résumé
The low-density lipoprotein receptor-related protein 1 (LRP-1) is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. In the field of cancer, LRP-1-mediated endocytosis was first associated with antitumor properties. However, recent results suggested that LRP-1 may coordinate the adhesion-deadhesion balance in malignant cells to support tumor progression. Here, we observed that LRP-1 silencing or RAP (receptor-associated protein) treatment led to accumulation of CD44 at the tumor cell surface. Moreover, we evidenced a tight interaction between CD44 and LRP-1, not exclusively localized in lipid rafts. Overexpression of LRP-1-derived minireceptors indicated that the fourth ligand-binding cluster of LRP-1 is required to bind CD44. Labeling of CD44 with EEA1 and LAMP-1 showed that internalized CD44 is routed through early endosomes toward lysosomes in a LRP-1-dependent pathway. LRP-1-mediated internalization of CD44 was highly reduced under hyperosmotic conditions but poorly affected by membrane cholesterol depletion, revealing that it proceeds mostly via clathrin-coated pits. Finally, we demonstrated that CD44 silencing abolishes RAP-induced tumor cell attachment, revealing that cell surface accumulation of CD44 under LRP-1 blockade is mainly responsible for the stimulation of tumor cell adhesion. Altogether, our data shed light on the LRP-1-mediated internalization of CD44 that appeared critical to define the adhesive properties of tumor cells.
Référence
Mol Cell Biol. 2012 Aug;32(16):3293-307