Vascular smooth muscle cell (SMC) proliferation and migration are important events in the development of atherosclerosis. The low-density lipoprotein receptor-related protein (LRP1) mediates suppression of SMC migration induced by platelet-derived growth factor (PDGF). Here we show that LRP1 forms a complex with the PDGF receptor (PDGFR). Inactivation of LRP1 in vascular SMCs of mice causes PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.

The low density lipoprotein (LDL) receptor gene family represents a class of multifunctional, endocytic cell surface receptors. Recently, roles in cellular signaling have also emerged. For instance, the very low density lipoprotein receptor (VLDLR) and the apolipoprotein receptor-2 (apoER2) function in a developmental signaling pathway that regulates the lamination of cortical layers in the brain and involves the activation of tyrosine kinases. Furthermore, the cytoplasmic domain of the LDL receptor-related protein (LRP) was found to be a substrate for the non-receptor tyrosine kinase Src, but the physiological significance of this phosphorylation event remained unknown. Here we show that tyrosine phosphorylation of LRP occurs in caveolae and involves the platelet-derived growth factor (PDGF) receptor ␤ and phosphoinositide 3-kinase. Receptor-associated protein, an antagonist of ligand binding to LRP, and apoE-enriched ␤-VLDL, a ligand for LRP, reduce PDGFinduced tyrosine phosphorylation of the LRP cytoplasmic domain. In the accompanying paper (Loukinova, E., Ranganathan, S., Kuznetsov, S., Gorlatova, N., Migliorini, M., Ulery, P. The low density lipoprotein (LDL) 1 receptor-related protein (LRP) is a member of an ancient and multifunctional gene family that has arisen during the transition from unicellular to multicellular organisms (1). The namesake of this family is the LDL receptor, an endocytic cell surface receptor that controls plasma cholesterol levels by removing cholesterol-rich LDL particles from the circulation via the liver. LRP also participates in the removal of a specific class of lipoprotein particles, the chylomicron remnants, by the liver. However, lipoprotein clearance is only one function of LRP. At present over 30 different ligands are known that interact with this multifunctional receptor (2). Most of the known ligands fall into two classes, depending on whether they function in lipid metabolism or in the regulation of extracellular protease activity.Much of what we know about the biological functions of LRP has been derived from the study of its role in ligand endocytosis and the routing of the endocytosed ligands toward lysosomal degradation. However, recently increasing evidence has accumulated that suggests that LRP is likely involved in transducing extracellular signals to the cell. First, two other members of the LDL receptor gene family, the very low density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor-2 (apoER2) have been found to be obligate components of a developmental signaling pathway that regulates the lamination of the cortex and of the cerebellum (3). Signaling by the VLDLR and apoER2 ligand Reelin involves the activation of tyrosine kinases and subsequent phosphorylation of the phosphotyrosine binding (PTB) domain containing adaptor protein Disabled-1 in the migrating neurons (4, 5). Second, several ligands for LRP, e.g. urokinase-type plasminogen activator, activated ␣2-macroglobulin, and thrombospondin (TSP), have been shown to activate distinct and dif...

The low-density lipoprotein (LDL) receptor is the founding member of a family of seven structurally closely related transmembrane proteins (LRP1, LRP1b, megalin/LRP2, LDL receptor, very low-density lipoprotein receptor, MEGF7/LRP4, LRP8/apolipoprotein E receptor2). These proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins. While currently available data suggest that the role of the LDL receptor is limited to the regulation of cholesterol homeostasis by receptor-mediated endocytosis of lipoprotein particles, there is growing experimental evidence that the other members of the gene family have additional physiological functions as signal transducers. In this review, we focus on the latest discovered functions of two major members of this family, LRP1 and megalin/LRP2, and on the newly elucidated physiological role of a third member of the family, MEGF7/LRP4, which can also function as a modulator of diverse signaling pathways during development.

The low-density lipoprotein receptor-related protein LRP1 is a cell surface receptor with functions in diverse physiological pathways, including lipid metabolism. Here we show that LRP1-deficient fibroblasts accumulate high levels of intracellular cholesterol and cholesteryl-ester when stimulated for adipocyte differentiation. We demonstrate that LRP1 stimulates a canonical Wnt5a signaling pathway that prevents cholesterol accumulation. Moreover, we show that LRP1 is required for lipolysis and stimulates fatty acid synthesis independently of the noradrenergic pathway, through inhibition of GSK3␤ and its previously unknown target acetyl-CoA carboxylase (ACC). As a result of ACC inhibition, mature LRP1-deficient adipocytes of adult mice are hypotrophic, and lower uptake of fatty acids into adipose tissue leads to their redistribution to the liver. These results establish LRP1 as a novel integrator of adipogenic differentiation and fat storage signals.The number of adipocytes in an organism is determined by a tightly regulated differentiation process of fibroblast-like preadipocytes (1, 2). Fat cell differentiation (adipogenesis) is controlled by hormonal-induced coordinated expression and activation of two main groups of transcription factors, the CCAAT/enhancer-binding protein (C/EBP) family and peroxisome proliferator-activated receptor ␥ (PPAR␥) 4 (2). PPAR␥, a member of the nuclear hormone receptors superfamily, is a crucial component of this cascade, as adipogenesis is impaired in PPAR␥-deficient mesenchymal stem cells (3). Activation of PPAR␥ induces the expression of lipogenic genes, such as adipocyte fatty acid-binding protein (422/aP2) (4), CD36 and lipoprotein lipase (LPL) (5). Accumulation of intracellular triglyceride (TG) droplets ultimately gives rise to the morphologically distinct fat cell (2). During periods of caloric restriction, TGs stored in adipocytes are catabolized into glycerol and fatty acids, to provide energy. Mobilization of lipids involves the sequential activation of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) (6), two lipolytic enzymes responsible for more than 95% of the TG hydrolase activity in the adipose tissues of mammals (7). The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor. Two NPXY motifs in the intracellular domain (ICD) serve as docking sites for several cytoplasmic adaptor proteins including Shc, Disabled-1, JIP1, PSD-95, CED-6/GULP, ARH, and Fe65, which control intracellular trafficking, as well as signaling events (8). LRP1 interacts with and mediates endocytosis of more than 40 unrelated ligands ranging from viruses to protease/protease inhibitor complexes, cytokines, and growth factors (9). In the liver, LRP1 and the LDL receptor (LDLr) share the endocytosis and subsequent degradation of TG-rich very-low-density lipoproteins and chylomicron remnants. However, endocytosis and clearance of macromolecules is only one function of LRP1. There is now substantial evidence that LRP1 also serves ...