Stephane Dedieu, Benoit Langlois, Herve Emonard and Laurent Martigny

Stéphane Dedieu by SINGER-POLIGNAC

The endocytic receptor LRP-1 as a versatile integrator of extracellular signals

Stéphane Dedieu, Benoît Langlois, Hervé Emonard, Laurent Martigny.

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a large multifunctional endocytic receptor mediating the clearance of various biological molecules from the extracellular matrix (ECM). In the field of cancer, LRP1-mediated endocytosis was first reported to decrease the accumulation of extracellular proteinases (MMPs, serine proteases) and to reduce the excessive remodeling of the ECM. LRP-1 was then widely associated to anti-tumor properties during the past decade and suggested as an attractive receptor for targeting the invasive behavior of malignant cells. However, the real functionalities connected to LRP-1 appear now much more complex and multifaceted. Using a long-term vector-based short hairpin RNA strategy against LRP-1, we indeed demonstrated that LRP-1 silencing prevents cell invasion, despite the high accumulation of proteolysis events associated to the tumor microenvironment. We highlighted that LRP1 contributes to cell attachment at the leading edge and cell detachment at the trailing edge to support cancer cell migration and invasion. In addition to its role in ligand binding and endocytosis, LRP-1 also regulates the focal adhesion disassembly, especially by targeting FAK and paxillin to focal complexes. The actin-cytoskeleton organization and dynamics of fast-invading tumor cells appeared also highly regulated by this cargo receptor. The following investigation revealed that LRP-1 β-chain constitutes a main docking site for focal adhesion components and mitogen-activated protein kinase-containing complexes. By regulating recruitment, activation and targeting of ERK and JNK to adhesion complexes in response to extracellular signals, LRP-1 maintains an adhesive state favorable for invasion. From our more recent data, we propose that LRP1 may also coordinate cell-matrix interactions in tumor cells by mediating the internalization of the hyaluronan receptor CD44 via the clathrin-coated vesicule pathway. Finally, a more complex model than that originally proposed emerges in which LRP-1 regulates the membrane proteome composition and dynamics and constitutes a key sensor of pericellular environment.