Demonstration of an activation regulated NF-κB/I-κBα complex in human platelets

Liu, Fengqi; Morris, Steve; Epps, Jerry L.; Carroll, Roger C.

doi:10.1016/s0049-3848(02)00130-5

Cited by 73 publications

(68 citation statements)

References 25 publications

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“…However, direct activation of PKC using PMA did induce VASP Ser157 phosphorylation, which was inhibited by H-89 (data not shown). PMA is a well known inducer of NFB activation in platelets, in a fashion similar to that of thrombin or collagen (20). 4 Based on these data, we conclude that PMA-induced VASP Ser157 phosphorylation in platelets is not mediated by PKC itself, but rather by PKC-dependent NFB activation followed by the release of active PKAc from an IB-PKAc complex.…”

Section: Discussionmentioning

confidence: 74%

“…Expression of NFB (p65) and IB␣ proteins, and their activation by thrombin and other agonists have been shown in platelets (20). During preparation of this report for publication, three reports concerning NFB expression and function in platelets were published (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

“…Expression of only some of the NFB family members has been demonstrated in platelets (20). Therefore we performed a more comprehensive examination of the protein and mRNA expression of the most common members of the NFB, IB, and IKK family in platelets, using HL-60 cells as a nucleated positive control (Fig.…”

Section: Analysis Of Intracellular Mechanisms Of Thrombin-and Collagementioning

confidence: 99%

“…Stimulation of cells with inducers of NFB activity dissociates NFB from IB, leading to IB degradation and release, and cAMP-independent activation of PKAc (15). The NFB complex plays a significant role in megakaryocyte differentiation and maturation (18 -19) and is also expressed in platelets (20), in which, however, no functional role has yet been identified.…”

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confidence: 99%

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Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Gambaryan

Kobsar

Rukoyatkina

et al. 2010

Journal of Biological Chemistry

130

134

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Protein kinase A (PKA) activation by cAMP phosphorylates multiple target proteins in numerous platelet inhibitory pathways that have a very important role in maintaining circulating platelets in a resting state. Here we show that in thrombin-and collagen-stimulated platelets, PKA is activated by cAMP-independent mechanisms involving dissociation of the catalytic subunit of PKA (PKAc) from an NFB-IB␣-PKAc complex. We demonstrate mRNA and protein expression for most of the NFB family members in platelets. From resting platelets, PKAc was co-immunoprecipitated with IB␣, and conversely, IB␣ was also co-immunoprecipitated with PKAc. This interaction was significantly reduced in thrombin-and collagen-stimulated platelets. Stimulation of platelets with thrombin-or collagen-activated IKK, at least partly by PI3 kinase-dependent pathways, leading to phosphorylation of IB␣, disruption of an IB␣-PKAc complex, and release of free, active PKAc, which phosphorylated VASP and other PKA substrates. IKK inhibitor inhibited thrombin-stimulated IkB␣ phosphorylation, PKAIkB␣ dissociation, and VASP phosphorylation, and potentiated integrin ␣IIb␤3 activation and the early phase of platelet aggregation. We conclude that thrombin and collagen not only cause platelet activation but also appear to fine-tune this response by initiating downstream NFB-dependent PKAc activation, as a novel feedback inhibitory signaling mechanism for preventing undesired platelet activation.Platelets are small anucleate cells derived from megakaryocytes in the bone marrow, in a process in which megakaryocyte cytoplasmic extensions into microvessels are sheared from their transendothelial stems by flowing blood (1-2). Platelets play a key role in the normal homeostatic process through their ability to rapidly adhere to activated and/or injured endothelium and subendothelial matrix proteins (platelet adhesion), and to other activated platelets (platelet aggregation). Many factors bind to specific platelet receptors and regulate signaling pathways, which promote or inhibit platelet adhesion, aggregation, and secretion. In vivo, circulating platelets are continually exposed to a variety of activating factors including collagen, fibrinogen, ADP, von Willebrand Factor (vWF), thrombin, and thromboxane (3-5), as well as inhibitory factors such as endothelial-derived nitric oxide (NO), prostacyclin (PG-I 2 ), and ADPase (3, 5-6). A strong equilibrium between the two opposing processes of platelet stimulation and inhibition is thought to be essential for normal platelet and vascular function. An impairment of this equilibrium will promote either thrombotic or bleeding disorders.In the initial steps of platelet activation, the platelet receptor glycoproteins (GP) 3 1b and GPVI interact with extracellular matrix (ECM) proteins, causing platelets to tether and roll on the injured endothelium or subendothelial ECM (5). Stimulation of these receptors triggers intracellular signaling cascades that activate integrin ␣IIb␤3 and induce the release of secondary mediators like A...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Intracellular Mechanisms Of Thrombin-and Collagementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Gambaryan

Kobsar

Rukoyatkina

et al. 2010

Journal of Biological Chemistry

130

134

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“…Liu et al 25 showed that IkB is phosphorylated in activated platelets; whereas, Malaver et al 26 showed that inhibiting IKK affects platelet function. These data suggest a role for IKK in platelets, but a mechanistic understanding is lacking.…”

Section: Introductionmentioning

confidence: 99%

IκB kinase phosphorylation of SNAP-23 controls platelet secretion

Karim

Zhang

Banerjee

et al. 2013

Blood

107

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Platelet secretion plays a key role in thrombosis, thus the platelet secretory machinery offers a unique target to modulate hemostasis. We report the regulation of platelet secretion via phosphorylation of SNAP-23 at Ser95. Phosphorylation of this t-soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) occurs upon activation of known elements of the platelet signaling cascades (ie, phospholipase C, phorylation, platelet secretion, and SNARE complex formation; but, had no effect on platelet morphology or other metrics of platelet activation. Consistently, SNAP-23 phosphorylation enhanced membrane fusion of SNARE-containing proteoliposomes. In vivo studies with IKK inhibitors or platelet-specific IKK-b knockout mice showed that blocking IKK-b activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis. (Blood. 2013;121(22):4567-4574)

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Acute non‐heparin‐induced thrombocytopenia during hemodiafiltration in a patient with multiple myeloma

Morita

Nakanishi

Masuda

et al. 2019

Clinical Case Reports

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Key Clinical Message This report demonstrates that not only heparin‐induced thrombocytopenia, but also hemodialysis conditions (platelet activation due to hemodiafiltration and heparin underdosing) may markedly reduce the platelet count and cause clotting in the hemodialysis circuit in patients in a hypercoagulable state. The clot prevention effects of bortezomib are therefore of great importance.

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Demonstration of an activation regulated NF-κB/I-κBα complex in human platelets

Cited by 73 publications

References 25 publications

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex

IκB kinase phosphorylation of SNAP-23 controls platelet secretion

Acute non‐heparin‐induced thrombocytopenia during hemodiafiltration in a patient with multiple myeloma

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