Roles of low-density lipoprotein receptor-related protein 1 in tumors

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, fibroblasts, neurons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1 CpG islands. Furthermore, a novel fusion gene, LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

Fig. 1

Structures of low-density lipoprotein receptor-related protein 1 (LRP1) and very low-density lipoprotein receptor (VLDLR). This Figure is modified from Figure 1 of a review written by Herz et al. [2]. The large extracellular ligand-binding subunit of LRP1 consists of 4 different ligand-binging clusters that contain 2, 8, 10, and 11 cysteine-rich ligand-binding repeats, respectively (red dots). Each cluster contains 1–4 epidermal growth factor (EGF) precursor homology domains, which include 2 cysteine-rich EGF repeats (blue circles) and 6 YWTD domains (blue lines). The cytoplasmic tail of LRP1 contains 2 NPXY motifs (marked with an asterisk). In addition, the cytoplasmic tail of LRP1 has 1 YXXL motif. Compared with LRP1, VLDLR is smaller. In addition, the O-linked sugar domain of VLDLR is enriched with serine and threonine residues (blue hexagon). Moreover, the cytoplasmic tail of VLDLR contains only 1 NPXY motif. Thus, the structure of LRP1 determines the endocytosis of ligands

Fig. 2

Low-density LRP1-mediated cell signaling pathways. LRP1 regulates several signaling pathways in a phosphorylation-dependent manner. These pathways are involved in several processes of tumorigenesis and progression. Binding of LRP1 to platelet-derived growth factor (PDGF) receptor activates the mitogen-activated protein kinase (MAPK) signaling pathway, which subsequently activates the extracellular signal-regulated kinase (ERK) pathway and inhibits c-jun N-terminal kinase (JNK), resulting in cancer cell invasion and proliferation. In addition, ERK increases the transcriptional levels of matrix metalloproteinase (MMP)-2 and MMP-9, which drive cancer cell invasion. LRP1 activates the serine/threonine protein kinase (AKT) signaling pathway and insulin receptor (IR), which inhibits cancer cell apoptosis. LRP1 binds to the novel extracellular heat shock protein 90 (eHsp90) and forms an eHsp90-LRP1 signaling complex, which stimulates glioblastoma multiforme cell motility and invasion via AKT-dependent phosphorylation at S897 (p-EphA2S897). The eHsp90 signaling regulates AKT activation and facilitates recruitment of LRP1 to the receptor tyrosine kinase EphA2