LRP-1--CD44, a new cell surface complex regulating tumor cell adhesion

Mol Cell Biol. 2012 Aug;32(16):3293-307. doi: 10.1128/MCB.00228-12. Epub 2012 Jun 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biotinylation
  • Cell Adhesion
  • Cell Line, Tumor
  • Cholesterol / metabolism
  • Densitometry / methods
  • Disease Progression
  • Endocytosis
  • Endosomes / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Humans
  • Hyaluronan Receptors / biosynthesis*
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Lysosomes / metabolism
  • Membrane Microdomains
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Plasmids / metabolism
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology


  • Hyaluronan Receptors
  • LRP1 protein, human
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Cholesterol