Nerve Growth Factor Induces Rapid Increases in Functional Cell Surface Low Density Lipoprotein Receptor-related Protein

Abstract

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that binds multiple ligands and is highly expressed in neurons. Several LRP ligands, including apolipoprotein E/lipoproteins and amyloid precursor protein, have been shown to participate either in Alzheimer's disease pathogenesis or pathology. However, factors that regulate LRP expression in neurons are unknown. In the current study, we analyzed the effects of nerve growth factor (NGF) treatment on LRP expression, distribution, and function within neurons in two neuronal cell lines. Our results show that NGF induces a rapid increase of cell surface LRP expression in a central nervous system-derived neuronal cell line, GT1-1 Trk, which was seen within 10 min and reached a maximum at about 1 h of NGF treatment. This increase of cell surface LRP expression is concomitant with an increase in the endocytic activity of LRP as measured via ligand uptake and degradation assays. We also found that the cytoplasmic tail of LRP is phosphorylated and that NGF rapidly increases the amount of phosphorylation. Furthermore, we detected a significant increase of LRP expression at the messenger RNA level following 24 h of NGF treatment. Both rapid and long term induction of LRP expression were also detected in peripheral nervous system-derived PC12 cells following NGF treatment. Taken together, our results demonstrate that NGF regulates LRP expression in neuronal cells.The low density lipoprotein receptor-related protein (LRP) 1 is a large multiligand endocytic receptor expressed abundantly in liver and brain (1). In brain, it is expressed by most if not all neurons and some glial cells (2-4). LRP is the largest endocytic receptor identified to date (ϳ600 kDa; see Ref. 5), synthesized as a single polypeptide chain and cleaved in the trans-Golgi into two subunits (6, 7). A 39-kDa receptor-associated protein (RAP) is a unique LRP ligand antagonist (8, 9), which can also bind and antagonize ligand binding to other low density lipoprotein receptor family members (10 -12).While LRP has been shown to have over 10 ligands (1), four of these (apolipoprotein E (apoE)/lipoproteins, ␣ 2 -macroglobulin (␣ 2 M*) complexed with or without the amyloid peptide (A␤), tissue factor pathway inhibitor (TFPI), and ␤-amyloid precursor protein (APP)) have been shown to participate either in Alzheimer's disease pathogenesis or pathology. For example, the ⑀4 allele of apoE is a major risk factor for late onset AD (13-15). While the mechanism for this association is not yet clear, apoE has been found to associate with both A␤ and Tau both in vivo and in vitro (16 -19), and recent data suggest that apoE/lipoprotein uptake through neuronal LRP can modify toxic effects of A␤ (20). In addition, studies have shown that isoforms of apoE when conjugated to lipoproteins can differentially influence neurite outgrowth via cell surface LRP (21-24). ␣ 2 M is one of several constituents of A␤-containing plaques in AD brain (25,26). We and others have recently found that ␣ 2 M compl...

Circulating nerve growth factor levels in relation to obesity and the metabolic syndrome in women

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Platelet-derived Growth Factor Mediates Tyrosine Phosphorylation of the Cytoplasmic Domain of the Low Density Lipoprotein Receptor-related Protein in Caveolae

“…These experiments revealed that LRP can undergo phosphorylation in untransfected cultured cells under steady-state conditions, but they did not determine whether these phosphorylation events include tyro-sine residues. Phosphorylation of the LRP tail by serine/threonine kinases had previously been reported (26). To address this question and to determine whether the coprecipitated 60-kDa protein may also be phosphorylated on tyrosine residues, we immunoprecipitated LRP from J774 cells that had been treated (Fig.…”