LRP-1 Promotes Cancer Cell Invasion by Supporting ERK and Inhibiting JNK Signaling Pathways

Abstract

BackgroundThe 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 FindingsThrough 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.ConclusionsWe identified ERK and JNK as the main molecular relays by which LRP-1 regulates focal adhesion disassembly of malignant cells to support invasion.

LRP-1–CD44, a New Cell Surface Complex Regulating Tumor Cell Adhesion

“…‫,ءء‬ P Ͻ 0.01. consistent with the ability of LRP-1 to control signaling pathways, contributing to the aggressive behavior of tumor cells. We have recently demonstrated that LRP-1 sustains tumor progression by mediating the induction of an ERK cascade and inhibition of JNK phosphorylation in thyroid carcinoma (28). Others have shown that binding of the protease nexin 1 to LRP-1 stimulates the ERK pathway, leading to matrix metalloproteinase 9 (MMP-9) expression and metastasis development (17).…”

“…We recently characterized the intracellular molecular signaling relays involved in the LRP-1-mediated stimulation of cancer cell invasion (28). We thus identified the LRP-1 ␤-chain as a main docking site for mitogen-acti- (Fig.…”

Identification and Functional Analysis of Differentially Expressed Genes Related to Metastatic Osteosarcoma

“…LRP1 is a ubiquitously expressed endocytic receptor belonging to the LDL-receptor family (Herzand Strickland, 2001). LRP-1 can promote cancer cell invasion via supporting ERK and inhibiting JNK signaling pathways (Langlois et al, 2010), and has been identified as a molecular signaling partner for plateletderived growth factor receptor (PDGFR) (Boucherand Gotthardt, 2004). Moreover, PDGFR is considered as a therapeutic target and a prognostic marker for imatinib mesylate therapy in OS (Kubo et al, 2008).…”

Phase I Study of GRN1005 in Recurrent Malignant Glioma

“…Subsequent protein homology searches identified a 19-amino-acid sequence called Angiopep-2 that exhibits high transcytosis capacity (18), crossed the BBB through an LRP-1-mediated mechanism (25), and distributed broadly throughout brain parenchyma (18,26). In addition to its well-determined role in ligand binding and endocytosis, LRP-1 has emerged as a central molecular regulator of cytoskeleton organization and adhesive complex turnover in malignant cells (27).…”