The role of alternative splicing and C-terminal amino acids in thromboxane receptor stabilization

Valentin, François; Tippins, John R.; Field, Mark C.

doi:10.1016/j.bbrc.2005.02.058

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…The TPα splice variant, despite differential tissue expression and signalling properties, undergoes a similar translocation and stabilization essentially indistinguishable from the β-splice variant. Further, four arginine residues between the C-terminal-most trans-membrane region and the C-terminus of TPβ are required for responsiveness to hydrogen peroxide [12]. From these data it appeared that only a very limited population of thromboxane receptors existed on the plasma membrane of COS-7 and human coronary artery smooth muscle cells in the resting state.…”

Section: Introductionmentioning

confidence: 97%

Regulation of Thromboxane Receptor Signaling at Multiple Levels by Oxidative Stress-Induced Stabilization, Relocation and Enhanced Responsiveness

2010

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BackgroundThromboxane A2 (TxA2) is a major, unstable arachidonic acid metabolite, and plays a key role in normal physiology and control of vascular tone. The human thromboxane receptor (TPβ), expressed in COS-7 cells, is located predominantly in the endoplasmic reticulum (ER). Brief hydrogen peroxide exposure increases the efficiency of translocation of TPβ from the ER into the Golgi complex, inducing maturation and stabilization of TPβ. However, the ultimate fate of this post-ER TPβ pool is not known, nor is its capacity to initiate signal transduction. Here we specifically assessed if functional TPβ was transported to the plasma membrane following H2O2 exposure.ResultsWe demonstrate, by biotinylation and confocal microscopy, that exposure to H2O2 results in rapid delivery of a cohort of TPβ to the cell surface, which is stable for at least eight hours. Surface delivery is brefeldin A-sensitive, indicating that translocation of this receptor cohort is from internal pools and via the Golgi complex. H2O2 treatment results in potentiation of the increase to intracellular calcium concentrations in response to TPβ agonists U46619 and 8-iso PGF2α and also in the loss of ligand-dependent receptor internalization. Further there is increased responsiveness to a second application of the agonist. Finally we demonstrate that the effect of H2O2 on stimulating surface delivery is shared with the FP prostanoid receptor but not the EP3 or EP4 receptors.Conclusions/SignificanceIn summary, brief exposure to H2O2 results in an immediate and sustained increase in the surface pool of thromboxane receptor that is capable of mediating a persistent hyper-responsiveness of the cell and suggests a highly sophisticated mechanism for rapidly regulating thromboxane signaling.

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Section: Introductionmentioning

confidence: 97%

Regulation of Thromboxane Receptor Signaling at Multiple Levels by Oxidative Stress-Induced Stabilization, Relocation and Enhanced Responsiveness

2010

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“…Furthermore, promoter 3 is activated through activator protein-1 (AP-1) and OCT-1/-2 binding elements [ 26 ]. In addition, oxidative stress promotes the translocation of TPβ from the endoplasmic reticulum to the Golgi complex and ultimately into the plasma membrane [ 74 , 75 ]. Oxidative stress induces maturation and stabilization of the TPβ protein, prolonging protein half-life.…”

Section: Txa 2 Signaling In Cancermentioning

confidence: 99%

The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection

et al. 2022

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Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.

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Preparing to strike: Acute events in signaling by the serpentine receptor for thromboxane A2

Ashton

2023

Pharmacology & Therapeutics

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The role of alternative splicing and C-terminal amino acids in thromboxane receptor stabilization

Cited by 3 publications

References 25 publications

Regulation of Thromboxane Receptor Signaling at Multiple Levels by Oxidative Stress-Induced Stabilization, Relocation and Enhanced Responsiveness

Regulation of Thromboxane Receptor Signaling at Multiple Levels by Oxidative Stress-Induced Stabilization, Relocation and Enhanced Responsiveness

The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection

Preparing to strike: Acute events in signaling by the serpentine receptor for thromboxane A2

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