Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Singh, Inderpreet; Knezevic, Nebojsa Nick; Ahmmed, Gias U.; Kini, Vidisha; Malik, Asrar B.; Mehta, Dolly

doi:10.1074/jbc.m608288200

Cited by 202 publications

(228 citation statements)

References 47 publications

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“…42,50,51 The finding that GP-2A inhibited ␣v␤6-dependent TGF-␤ activity in a concentration-dependent manner supports the hypothesis that G␣ q is responsible for LPA-induced ␣v␤6 integrin-mediated TGF-␤. G␣ q can activate RhoA in a number of cells including MEFs, 49 platelets 52 and endothelial cells, [53][54][55] although as far as we are aware this is the first report of this effect in primary epithelial cells.…”

Section: Discussionmentioning

confidence: 83%

Lysophosphatidic Acid Induces αvβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein Gαq

Porte

Knox

et al. 2009

The American Journal of Pathology

196

156

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Activation of latent transforming growth factor ␤ (TGF-␤) by ␣v␤6 integrin is critical in the pathogenesis of lung injury and fibrosis. We have previously demonstrated that the stimulation of protease activated receptor 1 promotes ␣v␤6 integrin-mediated TGF-␤ activation via RhoA, which is known to modulate cell contraction. However, whether other G protein-coupled receptors can also induce ␣v␤6 integrinmediated TGF-␤ activation is unknown; in addition, the ␣v␤6 integrin signaling pathway has not yet been fully characterized. In this study, we show that lysophosphatidic acid (LPA) induces ␣v␤6-mediated TGF-␤ activation in human epithelial cells via both RhoA and Rho kinase. Furthermore, we demonstrate that LPA-induced ␣v␤6 integrin-mediated TGF-␤ activity is mediated via the LPA2 receptor, which signals via G␣ q . Finally, we show that the expression levels of both the LPA2 receptor and ␣v␤6 integrin are upregulated and are spatially and temporally associated following bleomycin-induced lung injury. Furthermore, both the LPA2 receptor and ␣v␤6 integrin are up-regulated in the overlying epithelial areas of fibrosis in patients with usual interstitial pneumonia. These studies demonstrate that LPA induces ␣v␤6 integrin-mediated TGF-␤ activation in epithelial cells via LPA2 , G␣ q , RhoA , and Rho kinase , and that this pathway might be clinically relevant to the development of lung injury and fibrosis. (Am J Pathol

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Section: Discussionmentioning

confidence: 83%

Lysophosphatidic Acid Induces αvβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein Gαq

Porte

Knox

et al. 2009

The American Journal of Pathology

196

156

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“…An increase in [Ca 2 + ] i has also been associated with activation of small GTPase RhoA. The inflammatory mediator such as thrombin is known to induce receptormediated Ca 2 + entry followed by RhoA activation, thereby resulting in increased endothelial permeability (390).…”

Section: A Altered Intracellular Ca 2 + Regulationmentioning

confidence: 99%

Reactive Oxygen Species in Inflammation and Tissue Injury

Mittal

Siddiqui

Tran

et al. 2014

Antioxidants & Redox Signaling

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3,620

2,424

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Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126-1167.

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“…Calcineurin activation in podocytes has, in turn, been implicated in mediating proteinuria in several murine models (33), whereas forced expression of constitutively active NFATc1 in podocytes rapidly leads to podocyte effacement and proteinuria (34). In addition to activating calcineurin, TRPC6 activates the small GTPase Rho, while antagonizing the activation of Rac, in podocytes and other cell types (35)(36)(37). Excess Rho activity in podocytes induces proteinuria and glomerular dysfunction (38,39).…”

Section: Gain-of-function Mutations In the Canonical Transient Receptmentioning

confidence: 99%

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Chiluiza

Krishna

Schumacher

et al. 2013

Journal of Biological Chemistry

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Background: Signaling events affected by disease-associated mutations in TRPC6 are poorly defined. Results: Expression of mutant TRPC6 induces ERK1/2 activation via both cell-autonomous and non-cell-autonomous mechanisms. Conclusion: Mutant TRPC6 activates complex signaling pathways that lead to the release of paracrine factors activating ERK. Significance: Understanding the signaling pathways downstream of gain-of-function TRPC6 is crucial for understanding TRPC6-mediated biology and pathology.

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Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Cited by 202 publications

References 47 publications

Lysophosphatidic Acid Induces αvβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein Gαq

Lysophosphatidic Acid Induces αvβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein Gαq

Reactive Oxygen Species in Inflammation and Tissue Injury

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

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