Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Moraes, Leonardo A.; Swales, Karen E.; Wray, Jessica A.; Damazo, Amílcar Sabino; Gibbins, Jonathan M.; Warner, Timothy D.; Bishop‐Bailey, David

doi:10.1182/blood-2006-05-022566

Cited by 76 publications

(90 citation statements)

References 23 publications

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“…Thus, protein-protein interaction with factors other than nuclear receptors has been suggested as an important regulatory mechanism for subcellular localization of nuclear receptors. Calreticulin mediates cytoplasmic localization of GR independently of classic leucine-rich NES (56), whereas RXR␣ is capable of binding to cytoplasmic G protein (21). The cytoplasmic accumulation of RAR␥ is unlikely due to increased nuclear export of the receptor protein because blocking Crm-1-mediated nuclear export with LMB had no effect on its cytoplasmic localization (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, certain rapid retinoid responses, such as activation of GTPase Rac (21), protein kinase C (22), and ERK2 (23), and phosphorylation of cAMP-response element-binding protein (24,25), cannot be explained by classic transcriptional regulation. Thus, subcellular localization of retinoid receptors changes during development of the testes (26) and during various stages of the menstrual cycle (27).…”

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confidence: 99%

“…Nur77 migrates from the nucleus to the cytoplasm where it targets mitochondria by binding to Bcl-2 (34 -36), providing a molecular basis for integration of nuclear receptor signaling to mitochondrial apoptotic machinery. RXR rapidly inhibits Rac activation and intracellular calcium release by binding to G protein G q in human platelets that contain no nucleus (21). RXR migrates from the nucleus to the cytoplasm during nerve growth factor-induced PC12 cell differentiation (30) and targets mitochondria to induce apoptosis (29).…”

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confidence: 99%

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A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

Han

Zhou

Kim

et al. 2009

Journal of Biological Chemistry

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Recent evidence suggests that extranuclear action of retinoid receptors is involved in mediating the pleiotropic effects of retinoids. However, whether they reside in the cytoplasm remains elusive. Here, we showed that retinoic acid receptor-␥ (RAR␥) was cytoplasmic in confluent cells, or when cells were released from serum depletion or treated with growth factors. In studying the regulation of RAR␥ subcellular localization, we observed that ectopically overexpressed RAR␥ was mainly cytoplasmic irrespective of serum concentration and cell density. The cytoplasmic retention of RAR␥ was inhibited by ligand retinoic acid (RA). In addition, coexpression of retinoid X receptor-␣ (RXR␣) resulted in nuclear localization of RAR␥ through their heterodimerization. Mutagenesis studies revealed that a C-terminal fragment of RXR␣ potently prevents RA-induced RAR␥ nuclear localization and transcriptional function. Furthermore, our results showed that the cytoplasmic retention of RAR␥ was due to the presence of its unique N-terminal A/B domain, which was subject to regulation by p38 MAPK-mediated phosphorylation. Deletion or mutation of the N-terminal A/B domain largely impaired its cytoplasmic localization. Together, our data demonstrate that the subcellular localization of RAR␥ is regulated by complex interactions among ligand binding, receptor phosphorylation, and receptor dimerizations.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

Han

Zhou

Kim

et al. 2009

Journal of Biological Chemistry

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“…NFB now appears, like several other transcription factors including peroxisome proliferator-activated receptor (48), steroid (49), and glucocorticoid receptors (50), and others, to be expressed in platelets and involved in diverse platelet functions. Most of the NFB transcription factor family members interact with and may regulate functions of other proteins.…”

Section: Discussionmentioning

confidence: 99%

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

131

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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“…RXR, RXR, PPAR, PPAR and the glucocorticoid receptor are present and rapidly inhibit platelet activation [11][12][13][14]. RXR was found to rapidly bind and inhibit the heterotrimeric G-protein Gq in a ligand dependent manner, potentially through the presence of an LXXLL motif found in the Gq family [14].…”

Section: Non-genomicmentioning

confidence: 99%

Nuclear Receptors in Vascular Biology

Bishop‐Bailey

2015

Curr Atheroscler Rep

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Nuclear receptors sense a diverse group of steroids and hormones (estrogens, progesterone, androgens, glucocorticoid and mineralocorticoid), vitamins (A and D), lipid metabolites, carbohydrates and xenobiotics. In response to these diverse but critically important mediators, nuclear receptors regulate the homeostatic control of lipids, carbohydrate, cholesterol and xenobiotic drug metabolism, inflammation, cell differentiation and development, including vascular development. The nuclear receptor family is one of the most important groups of signaling molecules in the body, and as such represent some of the most important established and emerging clinical and therapeutic targets. This review will highlight some of the emerging trends in nuclear receptor biology related to vascular biology.3

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Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Cited by 76 publications

References 23 publications

A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

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

Nuclear Receptors in Vascular Biology

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