Thrombospondin Mediates Calcium Mobilization in Fibroblasts via Its Arg-Gly-Asp and Carboxyl-terminal Domains

Tsao, Peter W.; Mousa, Shaker A.

doi:10.1074/jbc.270.40.23747

Cited by 44 publications

(37 citation statements)

References 48 publications

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“…The RGD effects were dose-dependent: increases were evident at 1 μM, minimally variable at 10 μM, and greatly reduced at 1 mM ( Fig.1H) (p<0.001 vs pretreatment control values at all three doses, TMT). This profile is consistent with evidence that RGD is a partial agonist which can have agonist or antagonist activities depending on dose (Tsao and Mousa, 1995).…”

Section: Integrin Ligands Increase [Ca 2+ ]I In Cortical Neuronssupporting

confidence: 89%

“…Different integrins regulate intracellular calcium levels in non-neuronal cells through effects on influx and release from intracellar stores (Sjaastad et al, 1994;Tsao and Mousa, 1995;Schottelndreier et al, 2001;Wu et al, 2001). The few studies of neurons show that integrin ligands increase calcium influx through effects on voltage-sensitive calcium channels (VSCCs) (Wildering et al, 2002;Gui et al, 2006) and NMDA receptors (Watson et al, 2007), effects that could have a profound influence on the calcium-dependent LTP induction process (Lynch et al, 1983;Rose and Konnerth, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

Lin

Hilgenberg

Smith

et al. 2008

Molecular and Cellular Neuroscience

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Integrins regulate cytoplasmic calcium levels ([Ca 2+ ]i) in various cell types but information on activities in neurons is limited. The issue is of current interest because of evidence that both integrins and changes in [Ca 2+ ]i are required for Long-Term Potentiation. Accordingly, the present studies evaluated integrin ligand effects in cortical neurons. Integrin ligands or α5ß1 integrin activating antisera rapidly increased [Ca 2+ ]i with effects greater in glutamatergic than GABAergic neurons, absent in astroglia, and blocked by ß1 integrin neutralizing antisera and the tyrosine kinase antagonist genistein. Increases depended upon extracellular calcium and intracellular store release. Ligandinduced effects were reduced by voltage-sensitive calcium channel and NMDA receptor antagonists, but blocked by tetrodotoxin or AMPA receptor antagonists. These results indicate that integrin ligation triggers AMPA receptor/depolarization-dependent calcium influx followed by intracellular store release and suggest the possibility that integrin modulation of activity-induced changes in [Ca 2+ ]i contributes importantly to lasting synaptic plasticity in forebrain neurons.

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Section: Integrin Ligands Increase [Ca 2+ ]I In Cortical Neuronssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

Lin

Hilgenberg

Smith

et al. 2008

Molecular and Cellular Neuroscience

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“…Significantly, indomethacin and NDGA had no effect, nor did calphostin c or BAPTA, protein kinase C inhibitors. Because BAPTA is a Ca ϩ2 chelator, it seems unlikely that the effect of 4N1K on SYK phosphorylation is mediated by Ca ϩ2 flux, a known action of IAP in other cell types (23,24). These data indicate that SYK phosphorylation occurs quite proximally to IAP activation and requires a heterotrimeric G i -like protein but not other downstream effectors of platelet activation.…”

Section: Resultsmentioning

confidence: 65%

Thrombspondin Acts via Integrin-associated Protein to Activate the Platelet Integrin αIIbβ3

Chung

Gao

Frazier

1997

Journal of Biological Chemistry

191

202

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Integrin-associated protein (IAP)1 is important in host defense where it is required for integrin-dependent functions of polymorphonuclear leukocytes (1). IAP also appears to be important in modulating integrin function in other cells (2) and in signal transduction upon ligand binding by certain integrins with which it associates (3, 4). We have recently discovered that IAP is a receptor for the COOH-terminal cell binding domain (CBD) of the thrombospondins (TSs) including TS1 (5), the most abundant protein of platelet ␣ granules (6). A peptide from the CBD, kRFYVVMWKk (4N1K) has been identified as an IAP agonist (2, 5). TS1 is thought to have a role in augmenting platelet aggregation (7,8). A mAb (C6.7) against the IAPbinding domain of TS1 can block secretion-dependent platelet aggregation (8), but the mechanism of this effect has remained obscure (9). IAP is present on platelets (10), but it was initially reported to have no functional role in platelet activation or aggregation (11). However, Dorahy et al. (12) have recently reported that the 4N1K agonist peptide, which we had identified in the CBD of TS1, can activate washed platelets causing their aggregation. In nucleated cells, IAP associates with ␣v␤3 and modulates its function (3, 4). For example, the CBD of TS1 and the 4N1K peptide stimulate the chemotaxis of endothelial cells on RGD-containing substrata, and this effect is blocked specifically by mAbs against IAP and ␣v␤3 (5). TS1, its CBD, and 4N1K peptide all stimulate the rapid spreading of C32 melanoma and NIH3T3 cells on sparse vitronectin substrata, which support only weak, slow spreading of these cells in the absence of TS1 (2). This stimulation of ␣v␤3-dependent spreading is specifically inhibited by pertussis toxin, indicating the participation of a heterotrimeric G i -like protein in a pathway linking IAP to a common cellular pathway resulting in protein kinase C activation, which leads to cell spreading (2) and motility (5). This sort of stimulation of an integrin-dependent function via G protein-dependent pathways is reminiscent of the costimulation of ␣IIb␤3 function in platelets by agents that act via heptahelical or seven transmembrane spanning receptors such as ADP, epinephrine, and thrombin (13, 14). Here we have examined the hypothesis that IAP ligation by TS1 has a role in modulating ␣IIb␤3 function. We find that IAP stimulation by its agonist 4N1K activates ␣IIb␤3 as judged by enhanced binding of the conformationally sensitive mAb PAC-1 (13-15) resulting in spreading of platelets on fibrinogen-coated surfaces, aggregation of stirred platelets (12), and assembly of a signaling complex containing IAP, the integrin, c-Src, FAK, and SYK. All of these actions of IAP are blocked by pertussis toxin, indicating the essential participation of a G i -like heterotrimeric G protein (2). In unstirred, washed platelets where the integrin is not engaged, 4N1K stimulates the tyrosine phosphorylation of SYK, an early event in platelet activation by many agonists (17). This activation of SYK is bloc...

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“…1,3 This pattern of short spicules corresponded to that predicted by surface tension analyses in WT erythrocytes, 37,38 and to that reported in response to Ca 2ϩ ionophore A23187 39 or ATP depletion. 3 TSP1-CD47 signaling was previously reported to include rapid cytosolic Ca 2ϩ mobilization, 40 cytoskeletal remodeling 41,42 and membrane PS externalization in various cell types. [42][43][44] CD47 may thus mediate similar effects in erythrocytes to enable those phenotypic changes.…”

Section: Tsp1 Triggers Discocyte Conversion Into Echinocyte In Connecmentioning

confidence: 99%

Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease

Camus

Gausserès

Bonnin

et al. 2012

Blood

112

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Patients with sickle cell disease suffer from painful crises associated with disseminated vaso-occlusions, increased circulating erythrocyte microparticles (MPs), and thrombospondin-1 (TSP1). MPs are submicron membrane vesicles shed by compromised or activated cells. We hypothesized that TSP1 mediates MP shedding and participates in vaso-occlusions. We injected TSP1 to transgenic SAD mice with sickle cell disease and characterized circulating phosphatidylserine؉ MPs by FACS. TSP1 stimulated MPs in plasma and initiated vaso-occlusions within minutes. In vitro, TSP1 triggered rapid erythrocyte conversion into spicule-covered echinocytes, followed by MP shedding. MP shedding was recapitulated by peptides derived from the TSP1 carboxyterminus. We purified MPs shed by erythrocytes in vitro and administered them back to SAD mice. MPs triggered immediate renal vaso-occlusions. In vitro, MPs triggered the production of radical oxygen species by endothelial monolayers, favored erythrocyte adhesion, and induced endothelial apoptosis. MPs also compromised vasodilation in perfused microvessels. These effects were inhibited by saturating MP phosphatidylserine with annexin-V, or with inhibitors of endothelial ROS production. We conclude that TSP1 triggers erythrocyte MP shedding. These MPs induce endothelial injury and facilitate acute vaso-occlusive events in transgenic SAD mice. This work supports a novel concept that toxic erythrocyte MPs may connect sickle cell anemia to vascular disease. (Blood. 2012;120(25): 5050-5058) IntroductionSickle cell disease (SCD) is a form of hemolytic anemia that results from a point mutation (HbS) in the gene of the globin ␤-chain. The mutation makes HbS susceptible to polymerize during hypoxic stress, producing long intracellular fibers that are responsible for drastic membrane and cytoskeletal remodeling. The HbS fibers polymerize and depolymerize in response to blood oxygenation and deoxygenation cycles. The repeated changes in red blood cell (RBC) shape cause a permanent loss of the biconcave phenotype, producing condensed cells with diverse degrees of crenation, and covered in cone-shaped membrane figures known as spicules. [1][2][3] The remodeled erythrocytes become progressively dehydrated and rigid. Fully and irreversibly remodeled erythrocytes are termed sickle erythrocytes with respect to their ultimate shape.Sickle erythrocytes display a strong predisposition to adhere to the endothelium, get trapped in small capillaries and reduce blood flow. Highly vascularized organs, such as kidneys, bones, and lungs are the seat of disseminated vascular occlusions and recurrent ischemic injury. 4 In some of these organs, ischemia causes extremely painful episodes termed vaso-occlusive crises (VOCs). These crises are attributed to stress factors, such as hypoxia, physical exercise, infection, trauma, or stress. However, the molecular basis for the development of vaso-occlusions in SCD has yet to be explained and several different triggers of VOCs may exist.After getting trapped in capillaries,...

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Thrombospondin Mediates Calcium Mobilization in Fibroblasts via Its Arg-Gly-Asp and Carboxyl-terminal Domains

Cited by 44 publications

References 48 publications

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

Thrombspondin Acts via Integrin-associated Protein to Activate the Platelet Integrin αIIbβ3

Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease

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