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LRP-1 promotes cancer cell invasion by supporting ERK and inhibiting JNK signaling pathways

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Langlois, Benoit Perrot, Gwenn Schneider, Christophe Henriet, Patrick [UCL] Emonard, Herve Dedieu, Stephane

Background: The low-density lipoprotein receptor-related protein-1 (LRP-1) is an endocytic receptor mediating the clearance of various extracellular molecules involved in the dissemination of cancer cells. LRP-1 thus appeared as an attractive receptor for targeting the invasive behavior of malignant cells. However, recent results suggest that LRP-1 may facilitate the development and growth of cancer metastases in vivo, but the precise contribution of the receptor during cancer progression remains to be elucidated. The lack of mechanistic insights into the intracellular signaling networks downstream of LRP-1 has prevented the understanding of its contribution towards cancer. Methodology/Principal Findings: Through a short-hairpin RNA-mediated silencing approach, we identified LRP-1 as a main regulator of ERK and JNK signaling in a tumor cell context. Co-immunoprecipitation experiments revealed that LRP-1 constitutes an intracellular docking site for MAPK containing complexes. By using pharmacological agents, constitutively active and dominant-negative kinases, we demonstrated that LRP-1 maintains malignant cells in an adhesive state that is favorable for invasion by activating ERK and inhibiting JNK. We further demonstrated that the LRP-1-dependent regulation of MAPK signaling organizes the cytoskeletal architecture and mediates adhesive complex turnover in cancer cells. Moreover, we found that LRP-1 is tethered to the actin network and to focal adhesion sites and controls ERK and JNK targeting to talin-rich structures. Conclusions: We identified ERK and JNK as the main molecular relays by which LRP-1 regulates focal adhesion disassembly of malignant cells to support invasion.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2010
Language Anglais
Journal information "PLoS One" - Vol. 5, no. 7, p. e11584 (2010)
Peer reviewed yes
Publisher Public Library of Science ((United States) San Francisco, CA)
e-issn 1932-6203
Publication status Publié
Affiliations UCL - SSS/DDUV - Institut de Duve
UCL - SSS/DDUV/CELL - Biologie cellulaire
UCL - (SLuc) Service de biochimie médicale
MESH Subject Signal Transduction - genetics - physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Microscopy, Fluorescence ; LDL-Receptor Related Protein 1 - genetics - metabolism ; JNK Mitogen-Activated Protein Kinases - genetics - metabolism ; Immunoprecipitation ; Humans ; Extracellular Signal-Regulated MAP Kinases - genetics - metabolism ; Cell Line, Tumor ; Cell Adhesion - genetics - physiology ; Blotting, Western
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Bibliographic reference Langlois, Benoit ; Perrot, Gwenn ; Schneider, Christophe ; Henriet, Patrick ; Emonard, Herve ; et. al. LRP-1 promotes cancer cell invasion by supporting ERK and inhibiting JNK signaling pathways. In: PLoS One, Vol. 5, no. 7, p. e11584 (2010)
Permanent URL http://hdl.handle.net/2078.1/33639