LRP-1--CD44, a new cell surface complex regulating tumor cell adhesion.
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.
Université de Reims Champagne-Ardenne, Unité MEDyC, CNRS FRE 3481, Laboratoire SiRMa, Campus Moulin de la Housse, Reims, France.
Gwenn
G
Perrot
Benoit
B
Langlois
Jérôme
J
Devy
Albin
A
Jeanne
Laurie
L
Verzeaux
Sébastien
S
Almagro
Hervé
H
Sartelet
Cathy
C
Hachet
Christophe
C
Schneider
Emilie
E
Sick
Marion
M
David
Michel
M
Khrestchatisky
Hervé
H
Emonard
Laurent
L
Martiny
Stéphane
S
Dedieu
D019921:Biotinylation; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D003720:Densitometry / Q000379:methods; D018450:Disease Progression; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology
D018960:Hyaluronan Receptors; C475476:LRP1 protein, human; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D002784:Cholesterol