scholarly journals The Putative Tumor Suppressor LRP1B, a Novel Member of the Low Density Lipoprotein (LDL) Receptor Family, Exhibits Both Overlapping and Distinct Properties with the LDL Receptor-related Protein

2001 ◽  
Vol 276 (31) ◽  
pp. 28889-28896 ◽  
Author(s):  
Chun-Xiang Liu ◽  
Yonghe Li ◽  
Lynn M. Obermoeller-McCormick ◽  
Alan L. Schwartz ◽  
Guojun Bu
Keyword(s):  
Tumor Suppressor ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Related Protein ◽  
Putative Tumor Suppressor ◽  
Receptor Family

scholarly journals The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein

2007 ◽  
Vol 402 (1) ◽  
pp. 17-23 ◽  
Author(s):  
David R. Taylor ◽  
Nigel M. Hooper
Keyword(s):  
Prion Protein ◽  
Low Density Lipoprotein ◽  
Neuronal Cells ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Cellular Prion Protein ◽  
Low Density ◽  
Related Protein ◽  
Density Lipoprotein Receptor

PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

Tissue-type plasminogen activator-binding RNA aptamers inhibiting low-density lipoprotein receptor family-mediated internalisation

2015 ◽  
Vol 114 (07) ◽  
pp. 139-149 ◽  
Author(s):  
Kenneth A. Bøtkjær ◽  
Nicky Helsen ◽  
Peter A. Andreasen ◽  
Daniel M. Dupont ◽  
Nils Bjerregaard
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Clot Lysis ◽  
Low Density ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Receptor Family

SummaryRecombinant tissue-type plasminogen activator (tPA, trade name Alteplase), currently the only drug approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of cerebral ischaemic stroke, has been implicated in a number of adverse effects reportedly mediated by interactions with the low-density lipo-protein (LDL) family receptors, including neuronal cell death and an increased risk of cerebral haemorrhage. The tissue-type plasminogen activator is the principal initiator of thrombolysis in human physiology, an effect that is mediated directly via localised activation of the plasmin zymogen plasminogen at the surface of fibrin clots in the vascular lumen. Here, we sought to identify a ligand to tPA capable of inhibiting the relevant LDL family receptors without interfering with the fibrinolytic activity of tPA. Systematic evolution of ligands by exponential enrichment (SELEX) was employed to isolate tPA-binding RNA aptamers, which were characterised in biochemical assays of tPA association to low density lipoprotein receptor-related protein-1 (LRP-1, an LDL receptor family member); tPA-mediated in vitro and ex vivo clot lysis; and tPA-mediated plasminogen activation in the absence and presence of a stimulating soluble fibrin fragment. Two aptamers, K18 and K32, had minimal effects on clot lysis, but were able to efficiently inhibit tPA-LRP-1 association and LDL receptor family-mediated endocytosis in human vascular endothelial cells and astrocytes. These observations suggest that coadministration alongside tPA may be a viable strategy to improve the safety of thrombolytic treatment of cerebral ischaemic stroke by restricting tPA activity to the vascular lumen.

scholarly journals Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein

2003 ◽  
Vol 369 (2) ◽  
pp. 407-416 ◽  
Author(s):  
Ingrid A.M. RELOU ◽  
Liane A.B. BAX ◽  
Herman J.M. van RIJN ◽  
Jan-Willem N. AKKERMAN
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Site Specific ◽  
Receptor Associated Protein ◽  
G Protein Coupled ◽  
Receptor Family

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase implicated in signalling pathways mediated by integrins and G-protein-coupled receptors (GPCRs). Upon stimulation FAK is phosphorylated on six tyrosine residues. Here we report the site-specific phosphorylation by low-density lipoprotein (LDL), which is known to induce integrin-independent FAK phosphorylation, and compare this with the effect of thrombin, which phosphorylates FAK via integrin αIIbβ3. Stimulation with LDL reveals (i) a major role for Tyr-925 phosphorylation which surpasses the phosphorylation of the other residues, including Tyr-397, in rate and extent, (ii) αIIbβ3-independent phosphorylation of Tyr-925 and Tyr-397, and (iii) complex formation between FAK and the Src-kinase Fgr but not with c-Src. These patterns differ profoundly from those induced by thrombin. LDL-induced phosphorylation of Tyr-925 and Tyr-397 was inhibited by 60—75% by receptor-associated protein, an inhibitor of members of the LDL receptor family. Thus these findings reveal a novel mechanism of FAK phosphorylation by signalling cascades involving a member of the LDL receptor family.

scholarly journals Modulation of the low-density-lipoprotein-receptor-related protein and its relevance to chylomicron-remnant metabolism

1992 ◽  
Vol 288 (3) ◽  
pp. 791-794 ◽  
Author(s):  
A Szanto ◽  
S Balasubramaniam ◽  
P D Roach ◽  
P J Nestel
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Chylomicron Remnant ◽  
Related Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

Hepatic levels of the low-density-lipoprotein (LDL)-receptor-related protein (LRP) and the LDL receptor were measured in rats subjected to treatments known to affect the expression of the LDL receptor. Propylthiouracil decreased both hepatic LRP and LDL receptor expression by 30-40%. Thyroxine treatment increased LDL receptor levels by 3-fold without altering LRP levels. In contrast, 17 alpha-ethinyloestradiol decreased LRP by 50%, whereas the LDL receptor was increased 5-fold. Plasma chylomicrons and their remnants were decreased to insignificant levels with this treatment. In rats fed with cholesterol there was a significant increase in these particles in plasma (1.21 +/- 0.4 versus 5.71 +/- 0.4 mg/dl), whereas the expression of LRP was unaltered. In Watanabe heritable hyperlipidaemic and cholesterol-fed rabbits, in which the LDL receptor expression is absent or decreased, the expression of LRP was not significantly different from that in normal rabbits. These results suggest that the expression of hepatic LRP can be modulated by changes in the hormonal status of the rat and that this modulation is not tightly co-ordinated with that of the LDL receptor. Moreover, LRP does not appear to have a significant role in chylomicron-remnant clearance, whereas the LDL receptor is actively involved in this process.

scholarly journals Binding of Low Density Lipoprotein to Platelet Apolipoprotein E Receptor 2′ Results in Phosphorylation of p38MAPK

2004 ◽  
Vol 279 (50) ◽  
pp. 52526-52534 ◽  
Author(s):  
Suzanne J. A. Korporaal ◽  
Ingrid A. M. Relou ◽  
Miranda van Eck ◽  
Vera Strasser ◽  
Martineke Bezemer ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Family Member ◽  
Tyrosine Kinases ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Mitogen Activated Protein Kinase ◽  
Low Density ◽  
Platelet Surface ◽  
Receptor Family

Binding of low density lipoprotein (LDL) to platelets enhances platelet responsiveness to various aggregation-inducing agents. However, the identity of the platelet surface receptor for LDL is unknown. We have previously reported that binding of the LDL component apolipoprotein B100 to platelets induces rapid phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Here, we show that LDL-dependent activation of this kinase is inhibited by receptor-associated protein (RAP), an inhibitor of members of the LDL receptor family. Confocal microscopy revealed a high degree of co-localization of LDL and a splice variant of the LDL receptor family member apolipoprotein E receptor-2 (apoER2′) at the platelet surface, suggesting that apoER2′ may contribute to LDL-induced platelet signaling. Indeed, LDL was unable to induce p38MAPKactivation in platelets of apoER2-deficient mice. Furthermore, LDL bound efficiently to soluble apoER2′, and the transient LDL-induced activation of p38MAPKwas mimicked by an anti-apoER2 antibody. Association of LDL to platelets resulted in tyrosine phosphorylation of apoER2′, a process that was inhibited in the presence of PP1, an inhibitor of Src-like tyrosine kinases. Moreover, phosphorylated but not native apoER2′ co-precipitated with the Src family member Fgr. This suggests that exposure of platelets to LDL induces association of apoER2′ to Fgr, a kinase that is able to activate p38MAPK. In conclusion, our data indicate that apoER2′ contributes to LDL-dependent sensitization of platelets.

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