Identification of LRP-1 as an endocytosis and recycling receptor for β1-integrin in thyroid cancer cells

// Louis Theret 1, 2 , Albin Jeanne 1, 2, 3 , Benoit Langlois 1, 2 , Cathy Hachet 1, 2 , Marion David 4 , Michel Khrestchatisky 5 , Jérôme Devy 1, 2 , Emonard Hervé 1, 2 , Sébastien Almagro 1, 2 and Stéphane Dedieu 1, 2 1 Université de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Reims, France 2 CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France 3 SATT Nord, Lille, France 4 VECT-HORUS SAS, Faculté de Médecine Secteur Nord, Marseille, France 5 Aix Marseille Université, CNRS, NICN, Marseille, France Correspondence to: Stéphane Dedieu, email: stephane.dedieu@univ-reims.fr Keywords: LRP-1, β1-integrin, cancer, endocytosis, recycling Received: March 31, 2017 Accepted: July 25, 2017 Published: August 10, 2017 ABSTRACT LRP-1 is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP-1 was reported to control focal adhesion turnover to optimize the adhesion-deadhesion balance to support invasion. To better understand how LRP-1 coordinates cell-extracellular matrix interface, we explored its ability to regulate cell surface integrins in thyroid carcinomas. Using an antibody approach, we demonstrated that β1-integrin levels were increased at the plasma membrane under LRP1 silencing or upon RAP treatment, used as LRP-1 antagonist. Our data revealed that LRP-1 binds with both inactive and active β1-integrin conformations and identified the extracellular ligand-binding domains II or IV of LRP-1 as sufficient to bind β1-integrin. Using a recombinant β1-integrin, we demonstrated that LRP-1 acts as a regulator of β1-integrin intracellular traffic. Moreover, RAP or LRP-1 blocking antibodies decreased up to 36% the number of β1-integrin-containing endosomes. LRP-1 blockade did not significantly affect the levels of β1-integrin-containing lysosomes while decreasing localization of β1-integrin within Rab-11 positive vesicles. Overall, we identified an original molecular process in which LRP-1 acts as a main regulator of β1-integrin internalization and recycling in thyroid cancer cells.