Low Density Lipoprotein Receptor-related Protein Modulates the Expression of Tissue-type Plasminogen Activator in Human Colon Fibroblasts

Hardy, Medora M.; Feder, Joseph; Wolfe, Richard A.; Bu, Guojun

doi:10.1074/jbc.272.10.6812

Cited by 14 publications

(9 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, our recent data suggest that negative feedback regulation of tissue plasminogen activator expression in colon fibroblasts is mediated via cell surface LRP (63). These observations suggest that at least one LRP ligand may modulate its own synthesis through communication between LRP and the transcriptional machinery of the cell.…”

Section: Discussionmentioning

confidence: 98%

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

Bu¹,

Sun²,

Schwartz³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 98%

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

Bu¹,

Sun²,

Schwartz³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, several studies have shown that apoE3, a ligand of LRP, increases neurite extension via LRP (Bellosta et al, 1995;Holtzman et al, 1995;Narita et al, 1997). Second, our previous studies have shown that negative feedback regulation of tPA gene expression in colon fibroblasts is mediated via tPA interaction with cell surface LRP (Hardy et al, 1997). Third, recent studies have shown that the LRP tail interacts with a heterotrimeric GTP-binding protein (Goretzki and Mueller, 1998) and two cytoplasmic adaptor proteins, FE65 and mammalian Disabled (Trommsdorff et al, 1998).…”

Section: Discussionmentioning

confidence: 98%

Role of Tissue Plasminogen Activator Receptor LRP in Hippocampal Long-Term Potentiation

Zhuo¹,

et al. 2000

Self Cite

View full text Add to dashboard Cite

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and the beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.

show abstract

“…First, several studies have shown that apoE3, a ligand of LRP, increases neurite extension via LRP (1,11,23,37). Second, our previous studies have shown that negative feedback regulation of tissue plasminogen activator gene expression in colon fibroblasts is mediated via cell surface LRP (18). Third, studies have shown that the LRP tail interacts with a GTP-binding protein induces cAMP-dependent protein kinase activity (16).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Major Cyclic AMP-Dependent Protein Kinase A Phosphorylation Site within the Cytoplasmic Tail of the Low-Density Lipoprotein Receptor-Related Protein: Implication for Receptor-Mediated Endocytosis

Kerkhof

Marzolo

et al. 2001

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multiligand endocytic receptor that belongs to the LDL receptor family. Recently, studies have revealed new roles of LDL receptor family members as transducers of extracellular signals. Our previous studies have demonstrated LRP phosphorylation within its cytoplasmic tail, but the nature of LRP phosphorylation and its potential function was unknown. In the present study using both in vivo and in vitro analysis, we found that LRP phosphorylation is mediated by the cAMP-dependent protein kinase A (PKA). Using site-directed mutagenesis and LRP minireceptor constructs, we further identified the predominant LRP phosphorylation site at serine 76 of its cytoplasmic tail. Finally, we demonstrated that mutations of serine 76, which abolish LRP phosphorylation by PKA, result in a decrease in the initial endocytosis rate of LRP and a lower efficiency in delivery of ligand for degradation. Thus, the role of PKA phosphorylation of LRP in receptor-mediated endocytosis may provide a mechanism by which the endocytic function of LRP can be regulated by external signals.The low-density lipoprotein (LDL) receptor-related protein (LRP) is a member of the LDL receptor (LDLR) gene family, which also include in mammals: LDLR itself, the very-lowdensity lipoprotein receptor (VLDLR), megalin-LRP-2, apolipoprotein E receptor-2 (apoER2)-LR8B, and LR11-sorLA-1 (30,44,54,55). LRP is synthesized as a 600-kDa single-chain precursor, which undergoes posttranslational proteolytic processing within the trans-Golgi compartment by the endopeptidase furin (21,53). This posttranslational processing results in a formation of mature LRP as a noncovalently associated heterodimer, consisting of the extracellular 515-kDa chain and the transmembrane 85-kDa chain (21). The 515-kDa subunit contains all the putative ligand-binding domains including 31 copies of complement-type ligand-binding repeats arranged in four clusters of 2, 8, 10, and 11. In addition, there are 22 copies of the cysteine-rich epidermal growth factor (EGF)-type repeat flanking the ligand-binding clusters (30,44). The multiple domain structure of LRP provides potential binding sites for many structurally and functionally diverse ligands including apolipoprotein E-lipoproteins, ␣ 2 -macroglobulin, plasminogen activators, and ␤-amyloid precursor protein (7,30,44). Ligand interactions with LRP can be antagonized by a 39-kDa receptor-associated protein (RAP), a unique LRP ligand frequently used as a tool in the study of ligand-receptor interaction. RAP also functions intracellularly as a molecular chaperone for LRP and facilitates LRP folding and trafficking within the secretory pathway (7). Increasing evidence has shown that LRP plays important roles in lipoprotein remnant catabolism (52), protease regulation (49), cell migration (50, 51), neuronal process outgrowth (23), and the pathogenesis of Alzheimer's disease (29,48).Despite extensive studies on the extracellular domains of the LDLR members in ligand binding, inform...

show abstract

Low Density Lipoprotein Receptor-related Protein Modulates the Expression of Tissue-type Plasminogen Activator in Human Colon Fibroblasts

Cited by 14 publications

References 36 publications

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

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

Role of Tissue Plasminogen Activator Receptor LRP in Hippocampal Long-Term Potentiation

Identification of a Major Cyclic AMP-Dependent Protein Kinase A Phosphorylation Site within the Cytoplasmic Tail of the Low-Density Lipoprotein Receptor-Related Protein: Implication for Receptor-Mediated Endocytosis

Contact Info

Product

Resources

About