Interaction of β2-glycoprotein I with members of the low density lipoprotein receptor family

Pennings, Maarten; Lummel, Menno van; Derksen, R. H. W. M.; Urbanus, Rolf T.; Romijn, Roland A.; Lenting, Peter J.; Groot, Philip G. de

doi:10.1111/j.1538-7836.2006.02036.x

Cited by 71 publications

(79 citation statements)

References 42 publications

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“…As mentioned, the low-density lipoprotein (LDL) receptor-related protein-8 (LRP8; also known as ApoER2') and GPIbα appear also to play an important role in mediating the pathogenic effects of aPLA [63,64]. The interaction of dimerized β2GP1 with either ApoER2' or GPIbα was found to lower the threshold of platelet activation by collagen or fibronectin surfaces [31,65].…”

Section: Apoer2'and Gpibα As Apla Receptorsmentioning

confidence: 95%

“…The interaction of dimerized β2GP1 with either ApoER2' or GPIbα was found to lower the threshold of platelet activation by collagen or fibronectin surfaces [31,65]. While EC and monocytes do not express ApoER2', other members of LDL-receptor family were shown to bind the dimerized form of β2GP1 [64,66]. Further studies are needed to clarify the importance and mechanism by which GPIbα and LDL-receptor family of proteins may contribute to aPLA-mediated activation of target cell in APS.…”

Section: Apoer2'and Gpibα As Apla Receptorsmentioning

confidence: 99%

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Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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Section: Apoer2'and Gpibα As Apla Receptorsmentioning

confidence: 95%

Section: Apoer2'and Gpibα As Apla Receptorsmentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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“…Other receptors for b2-gpI are the low-density lipoprotein receptors (54), apoliprotein E receptor 2 (21), and megalin (19), although this latter molecule is unlikely because of its restriction to epithelial cells. Attachment of b2-gpI has also been ascribed to annexin A2 (20).…”

Section: Discussionmentioning

confidence: 99%

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Alard

Gaillard

Daridon

et al. 2010

The Journal of Immunology

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During the antiphospholipid syndrome, β2-gpI interacts with phospholipids on endothelial cell (EC) surface to allow the binding of autoantibodies. However, induced-pathogenic intracellular signals suggest that β2-gpI associates also with a receptor that is still not clearly identified. TLR2 and TLR4 have long been suspected, yet interactions between TLRs and β2-gpI have never been unequivocally proven. The aim of the study was to identify the TLR directly involved in the binding of β2-gpI on EC surface. β2-gpI was not synthesized and secreted by ECs in vitro, but rather taken up from FCS. This uptake occurred through association with TLR2 and TLR4 which partitioned together in the lipid rafts of ECs. After coimmunoprecipitation, mass-spectrometry identification of peptides demonstrated that TLR2, but not TLR4, was implicated in the β2-gpI retention. These results were further confirmed by plasmon resonance-based studies. Finally, siRNA were used to obtain TLR2-deficient ECs that lost their ability to bind biotinylated β2-gpI and to trigger downstream phosphorylation of kinases and activation of NFκB. TLR4 may upregulate TLR2 expression, thereby contributing to β2-gpI uptake. However, our data demonstrate that direct binding of β2-gpI on EC surface occurs through direct interaction with TLR2. Furthermore, signaling for anti–β2-gpI may be envisioned as a multiprotein complex concentrated in lipid rafts on the EC membrane.

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“…The studies by Pennings et al [14] are relevant not only because they help to delineate the molecular mechanisms triggered by APL antibodies. Understanding the nature of the receptor(s) and the interaction with b 2 GPI and APL/antib 2 GPI antibodies on target cells may help to devise new targeted modalities, that is, specific antibodies and/or antagonists that block the binding of the receptor to the ligand, for treatment and prevention of the clinical manifestations observed in patients with APS.…”

mentioning

confidence: 99%

“…In this issue of the Journal, Pennings and collaborators [14] elegantly show that dimeric b 2 GPI interacts with four other LDL-R family members: LDL-R related protein (LRP), megalin, the LDL-R. and the very low density lipoprotein receptor (VLDL-R). Utilizing deletion mutants, the interaction was found to be dependent on a binding site within domain V of b 2 GPI, which does not appear to overlap with the phospholipid-binding site within domain V. These receptorsfound ubiquitously in many cells -are anchored to the membrane via an intracellular tail and are capable of harboring endocytosis and intracellular signaling.…”

mentioning

confidence: 99%

In search for a receptor for antiphospholipid antibodies on target cells

Pierangeli

2006

Journal of Thrombosis and Haemostasis

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See also Pennings MTT, van Lummel M, Derksen RHWM, Urbanus RT, Romijn RA, Lenting PJ, de Groot PG. Interaction of b 2 -glycoprotein I with members of the low density lipoprotein receptor family. This issue, pp 1680-90. Antiphospholipid (APL) antibodies are associated with thrombosis and pregnancy loss and other clinical manifestations in patients with antiphospholipid syndrome (APS). APL antibodies are heterogeneous in function and specificity and recognize various protein antigens on the surface of target cells (i.e. platelets, endothelial cells, throphoblasts, monocytes). Among those, b 2 -glycoprotein I (b 2 GPI) seems to be the most relevant.APL/anti-b 2 GPI antibody binding to endothelial cell-bound b 2 GPI mediates various cell dysfunctions that are potentially important in determining different APS clinical manifestations. APL antibodies also have been shown to affect platelet activation. Recently, some of the intracellular pathways activated by APL antibodies in platelets, monocytes and endothelial cells have been examined. Studies have conclusively shown that APL antibodies induce phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in platelets, monocytes and endothelial cells, and activate the transcriptional factor nuclear factor-kappa B (NF-jB) in monocytes and endothelial cells [1][2][3][4][5].Although there is convincing evidence that APL antibodies can stimulate endothelial cells, monocytes and platelets, relatively little is known about the cell surface receptors that are engaged or crosslinked to induce intracellular signaling. In endothelial cells, there is indirect evidence that annexin A2, a receptor for tissue plasminogen activator (t-PA) and plasminogen, and toll-like receptor 4 (TLR-4), a receptor for bacterial lipopolysaccharide (LPS), may be binding b 2 -GPI and triggering intracellular signaling. Studies have recently shown that annexin A2 mediates endothelial cell activation by APL/antib 2 GPI antibodies after binding to b 2 GPI [6,7]. Because annexin A2 does not span the cell membrane, this interaction may require an ÔadaptorÕ protein able to transduce intracellular signaling. Raschi et al. [8] have previously shown that MyD88 signalling cascade -associated to TLR-4-is triggered by APL/ anti-b 2 GPI antibodies on the endothelial cell surface membrane. Zhang et al. [9] recently were able to identify a protein of 83 kDa that appeared to be TLR-4 among those that bound immobilized b 2 GPI by affinity-purification in Affi-Gel HZ columns followed by elution, sodium docecylsulfate polyacyrlamide gel electrophoresis (SDS-PAGE) and liquid chromatography with mass spectrometry (LC-MS) analysis. In recent studies, our group showed that APL/anti-b 2 GPI antibodies do not exert pathogenic effects in vivo in LPS non-responsive mice, indicating that TLR-4 may be a receptor for APL/anti-b 2 GPI antibodies in vivo [10].It is also possible that other molecules might act as receptors for b 2 GPI in various cell types. In previous studies, Lutters et al. [11] showed that APL/anti-b 2 ...

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Interaction of β2-glycoprotein I with members of the low density lipoprotein receptor family

Cited by 71 publications

References 42 publications

Receptors involved in cell activation by antiphospholipid antibodies

Receptors involved in cell activation by antiphospholipid antibodies

TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

In search for a receptor for antiphospholipid antibodies on target cells

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