Low Density Lipoprotein Phosphorylates the Focal Adhesion-associated Kinase p125FAK in Human Platelets Independent of Integrin αIIbβ3

Hackeng, Christian M.; Pladet, M W; Akkerman, Jan-Willem Ν.; Rijn, H. J. M. Van

doi:10.1074/jbc.274.1.384

Cited by 16 publications

(18 citation statements)

References 53 publications

(55 reference statements)

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“…This process is slow requiring 5 min or more and occurs through the rapid phosphorylation of p38 MAPK [18] . A second early event is the activation of p125 FAK [36,37] . At higher concentrations (3 g/l) and longer incubation times ( 1 4 h), LDL becomes an independent platelet activator triggering aggregation and secretion [26] .…”

Section: Ldl-induced Platelet Signalingmentioning

confidence: 99%

“…LDL-induced p125 FAK activation is only controlled by cAMP and is not changed in the presence of inhibitors of p38 MAPK phosphorylation, TxA 2 formation and activation of PKC or ERK1/2. Hence, LDL phosphorylates p125 FAK either downstream of TxA 2 formation and PKC and ERK1/2 activation, or through an independent pathway [36] . The mechanism of p125 FAK phosphorylation by LDL shows both similarities and differences with activation by integrin clustering or GPCR activation.…”

Section: Ldl-induced Phosphorylation Of P125mentioning

confidence: 99%

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Platelet Activation by Low Density Lipoprotein and High Density Lipoprotein

Korporaal

Akkerman²

2006

Pathophysiol Haemos Thromb

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Cardiovascular disease is the main cause of death and disability in the Western society. Lipoproteins are important in the development of cardiovascular disease since they change the properties of different cells involved in atherosclerosis and thrombosis. The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness. Several signaling pathways induced by LDL have been revealed in vitro, such as signaling via p38 mitogen-activated protein kinase and p125 focal adhesion kinase. High density lipoprotein (HDL) consists of two subtypes, HDL₂ and HDL₃, which have opposing effects on platelet activation. This review provides a summary of the activation of signaling pathways after platelet-LDL and platelet-HDL interaction, with special emphasis on their role in the development of thrombosis and atherosclerosis.

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Section: Ldl-induced Platelet Signalingmentioning

confidence: 99%

Section: Ldl-induced Phosphorylation Of P125mentioning

confidence: 99%

Platelet Activation by Low Density Lipoprotein and High Density Lipoprotein

Korporaal

Akkerman²

2006

Pathophysiol Haemos Thromb

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“…Binding of oxLDL to CD36 results in platelet activation through Src kinase and mitogen-activated protein kinase-dependent pathways, 9 although signaling through extracellular signal-regulated kinase and focal adhesion-associated kinase may also a play role. 8,10 Importantly, CD36 is key to both platelet hyperactivity and accelerated thrombosis in murine models of hyperlipidemia, effects that are mediated via oxidized lipids associated with oxLDL. 11 Thus, CD36 plays a prominent role in platelet activation in disease, although the signaling mechanism triggering platelet activity through CD36 remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways

Wraith

Magwenzi

Aburima

et al. 2013

Blood

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Key Points• Oxidized LDL stimulates rapid change in platelet shape through ligation of CD36.• Ligation of CD36 by oxidized LDL simultaneously activates tyrosine and Rho kinase-dependent signaling pathways.Oxidized low-density lipoproteins (oxLDL) generated in the hyperlipidemic state may contribute to unregulated platelet activation during thrombosis. Although the ability of oxLDL to activate platelets is established, the underlying signaling mechanisms remain obscure. We show that oxLDL stimulate platelet activation through phosphorylation of the regulatory light chains of the contractile protein myosin IIa (MLC). oxLDL, but not native LDL, induced shape change, spreading, and phosphorylation of MLC (serine 19) through a pathway that was ablated under conditions that blocked CD36 ligation or inhibited Src kinases, suggesting a tyrosine kinase-dependent mechanism. Consistent with this, oxLDL induced tyrosine phosphorylation of a number of proteins including Syk and phospholipase C g2. Inhibition of Syk, Ca 21 mobilization, and MLC kinase (MLCK) only partially inhibited MLC phosphorylation, suggesting the presence of a second pathway. oxLDL activated RhoA and RhoA kinase (ROCK) to induce inhibitory phosphorylation of MLC phosphatase (MLCP). Moreover, inhibition of Src kinases prevented the activation of RhoA and ROCK, indicating that oxLDL regulates contractile signaling through a tyrosine kinase-dependent pathway that induces MLC phosphorylation through the dual activation of MLCK and inhibition of MLCP. These data reveal new signaling events downstream of CD36 that are critical in promoting platelet aggregation by oxLDL. (Blood. 2013;122(4):580-589)

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“…53 Platelets from patients with Glanzmann thrombasthenia showed similar low density lipoproteininduced FAK phosphorylation as control platelets. 54 Integrinindependent phosphorylation of p125FAK has also been reported in platelets activated using immobilized human immunoglobulin G (IgG), an event that depends on Fc␥RII. 55 An intriguing finding was that p125FAK phosphorylation was detected in 2B-rVWF-dependent SIPA but not in WT-rVWFdependent SIPA.…”

Section: Discussionmentioning

confidence: 99%

Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of αIIbβ3 engagement

Mekrache

Bachelot‐Loza²,

Ajzenberg³

et al. 2003

Blood

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Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand factor (VWF) with both glycoprotein Ib (GPIb) and ␣IIb␤3 receptors. Type 2B recombinant VWF (2B-rVWF), characterized by an increased affinity for GPIb, induces strong SIPA at a high shear rate (4000 s ؊1 ). Despite the increased affinity of 2B-rVWF for GPIb, patients with type 2B von Willebrand disease have a paradoxical bleeding disorder, which is not well understood. The purpose of this study was to determine if SIPA induced by 2B-rVWF was associated with ␣IIb␤3-dependent platelet activation. To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPAdependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of ␣IIb␤3 blockers. At a high shear rate, 2B-rVWF induced a strong SIPA, as shown by a 92.7% ؎ 0.4% disappearance of single platelets (DSP) after 4.5 minutes. In these conditions, increased P-Tyr of proteins migrating at positions 64 kd, 72 kd, and 125 kd were observed. The band at 125 kd was identified as pp125FAK using anti-phospho-FAK antibody. This effect, which required a high level of SIPA (> 70% DSP), was observed at 4000 s ؊1 but not at 200 s ؊1 . Monoclonal antibodies (MoAbs) 6D1 (anti-GPIb) and 328 (anti-VWF A1 domain), completely abolished SIPA and p125FAK phosphorylation mediated by 2B-rVWF. In contrast, neither RGDS peptide nor MoAb 7E3, both known to block ␣IIb␤3 engagement, had any effect on SIPA and pp125FAK. The size of aggregates formed at a high shear rate in the presence of 2B-rVWF was decreased by genistein, demonstrating the biologic relevance of pp125FAK. These findings provide a unique mechanism whereby the enhanced interaction of 2B-rVWF with GPIb, without engagement of ␣IIb␤3, is sufficient to induce SIPA but does not lead to stable thrombus formation. IntroductionPlatelets play a critical role in the arrest of bleeding by adhering to vascular matrix proteins and to other activated platelets at sites of vessel wall injury. High shear rates generate forces between platelets and the damaged vessel wall that induce specific ligandreceptor interactions required for platelet adhesion, activation, and aggregation. A key adhesive protein initiating platelet-vessel wall interactions is the large multimeric protein, von Willebrand factor (VWF). When immobilized at the site of injury, VWF exhibits its A1 domain, allowing the capture of platelets from rapidly flowing blood by an interaction with the glycoprotein Ib/V/IX (GPIb/V/IX) complex. This binding generates signals leading to ␣IIb␤3 integrin activation which becomes competent to interact with VWF and to promote irreversible platelet adhesion. [1][2][3][4] In vitro, the change in VWF can be mimicked by the binding of VWF to its modulators ristocetin or botrocetin. 5,6 High shear rates are important not only in the initial contact of platelets with the vessel wall, but also in the process of platelet aggregation, where fluid-phase VWF is required to stabilize platelet-platelet interactions and...

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Low Density Lipoprotein Phosphorylates the Focal Adhesion-associated Kinase p125FAK in Human Platelets Independent of Integrin αIIbβ3

Cited by 16 publications

References 53 publications

Platelet Activation by Low Density Lipoprotein and High Density Lipoprotein

Platelet Activation by Low Density Lipoprotein and High Density Lipoprotein

Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways

Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of αIIbβ3 engagement

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