Common Signaling Pathways Link Activation of Murine PAR-1, LPA, and S1P Receptors to Proliferation of Astrocytes

Sorensen, Scott D.; Nicole, Olivier; Peavy, Richard D.; Montoya, Lisa M.; Lee, C. Justin; Murphy, Thomas J.; Traynelis, Stephen F.; Hepler, John R.

doi:10.1124/mol.64.5.1199

Cited by 193 publications

(180 citation statements)

References 57 publications

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“…4B). These findings confirm the previously reported ability of LPA, S1P, and thrombin to induce mitogenesis in primary astrocytes in culture (18). Thrombin-mediated [ 3 H]thymidine incorporation was found to be markedly reduced (66 Ϯ 2% inhibition) in PLC KO cells.…”

supporting

confidence: 81%

“…All four of these agonists were able to increase accumulation of inositol phosphates (InsPs) in primary mouse astrocytes, consistent with published findings (18).…”

supporting

confidence: 80%

“…S1P, LPA, or thrombin receptor activation induce prolonged ERK1/2 phosphorylation in primary astrocytes (18,29). Based on the findings above, we explored the possibility that PLC was involved in the regulation of ERK1/2 and specifically critical for sustained ERK signaling in response to thrombin.…”

mentioning

confidence: 99%

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Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Citro

Malik

Oestreich

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipase C (PLC ) has been suggested to transduce signals from small GTPases, but its biological function has not yet been clarified. Using astrocytes from PLC -deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphatidic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLC . Stimulation by lysophospholipids occurs through Gi, whereas thrombin activates PLC through Rho. Further studies reveal that PLC is required for thrombin-but not LPA-induced sustained ERK activation and DNA synthesis, providing a novel mechanism for GPCR and Rho signaling to cell proliferation. The requirement for PLC in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLC serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.mitogenesis ͉ small GTPases ͉ thrombin ͉ lysophospholipids ͉ guanine nucleotide exchange factor S timulation of a variety of cell surface receptor types, most prominently G protein-coupled receptors (GPCRs), leads to the activation of phospholipase C (PLC). Hydrolysis of phosphatidylinositol (4,5)bisphosphate (PIP 2 ) generates the second messengers inositol (1,4,5)trisphosphate (InsP 3 ) and diacylglycerol (DAG) (1). Thirteen mammalian PLC isozymes, divided into six families, have been identified. All contain conserved catalytic regions as well as subtype-specific domains that allow for a plethora of specific regulatory mechanisms. The best characterized of these are the PLC␤ family, regulated by direct binding of the heterotrimeric G protein subunits ␣ q and ␤␥, and PLC␥ regulated by receptor and nonreceptor protein tyrosine kinases (2).The same second messengers are generated by all of the PLCs. Thus, regardless of the extracellular signal-and PLC isoform-activated, InsP 3 will be formed and trigger Ca 2ϩ release from intracellular stores, and DAG accumulation will lead to activation of protein kinase C (3). Undoubtedly, there are distinct spatiotemporal aspects to the signals elicited by different receptors and classes of PLC, but it remains unclear why so many PLC isoforms, capable of generating the same signal, should exist.An emerging area in biology has been the recognition that many proteins identified on the basis of a particular activity serve additional functions. The regulators of G protein signaling (RGS) proteins are paradigmatic in this regard. These proteins contain not only canonical RGS sequences dedicated to GTP hydrolysis but also non-RGS domains and motifs with alternative functions. Thus, not only do they turn off GPCR signaling but in addition they can enhance small G protein activation, serve as effectors, and act as scaffold proteins (4). PLC , an isoform of PLC that was discovered fewer than 6 years ago, likewise has the structure of a multifunctional signaling protein (5-7). It contains not only PLC catalytic regions but also, in its N-terminal region, a CDC25 homology domain...

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supporting

confidence: 81%

“…All four of these agonists were able to increase accumulation of inositol phosphates (InsPs) in primary mouse astrocytes, consistent with published findings (18).…”

supporting

confidence: 80%

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Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Citro

Malik

Oestreich

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the four receptors identified to date, thrombin cleaves PAR1, PAR3, and PAR4, with the highest affinity for PAR1 (10 -12). PARs mediate blood clotting and mitogenic and chemotactic effects of thrombin via coupling to trimeric G proteins, mostly G i/o , G q/11 , and G 12/13 (13,14). Furthermore, the activation of different G proteins leads to stimulation of various phospholipases, particularly phospholipases C␤, resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the production of inositol 1,4,5-trisphosphate and diacylglycerol, which then causes Ca 2ϩ mobilization and PKC activation (15,16).…”

mentioning

confidence: 99%

Novel Role for p21-activated Kinase 2 in Thrombin-induced Monocyte Migration

Gadepalli

Kotla

Heckle

et al. 2013

Journal of Biological Chemistry

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“…We were enable to show that 1) similarly to astrocytes, O4 [34,35]. We focused on cortical astrocytes from P7 mice and SVZ-derived astrocytes from newborn mice, the last having occasionally PAR-1 expression, but both being insensitive to thrombin stimulation (see Supplementary Figure 1 B).…”

Section: Discussionmentioning

confidence: 99%

Functional Identification of Neural Stem Cell–Derived Oligodendrocytes by Means of Calcium Transients Elicited by Thrombin

Grade

Agasse

Bernardino

et al. 2010

Rejuvenation Research

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In this work, we questioned whether SVZ-derived oligodendrocytes could be functionally discriminated on the basis of intracellular calcium levels ( Thrombin-induced calcium increase in oligodendrocytes is mediated by protease-activated receptor-1 (PAR-1) activation and downstream signaling through G q/11 and phospholipase C (PLC), resulting in calcium recruitment from intracellular compartments.This method allows the analysis of functional properties of oligodendrocytes in living SVZ cultures, which is of major interest for the development of effective grafting strategies in the demyelinated brain. Additionally, it opens new perspectives for the search of new prooligodendrogenic factors to be used prior grafting.

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Common Signaling Pathways Link Activation of Murine PAR-1, LPA, and S1P Receptors to Proliferation of Astrocytes

Cited by 193 publications

References 57 publications

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Novel Role for p21-activated Kinase 2 in Thrombin-induced Monocyte Migration

Functional Identification of Neural Stem Cell–Derived Oligodendrocytes by Means of Calcium Transients Elicited by Thrombin

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