Critical roles for the actin cytoskeleton and cdc42 in regulating platelet integrinα2β1

Pula, Giordano; Poole, Alastair W.

doi:10.1080/09537100701777303

Cited by 29 publications

(29 citation statements)

References 36 publications

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“…Especially, the up-regulation of collagen type I, IV and V indicated that nickel ions may affect cell structure restoration through promoting the interaction of ECM receptors and generating hypoxia effect in the treated L-929 cells. CDC42, a regulator of cell cycle, can transfer cell signals related to the restoration of actin cytoskeleton and suppress the ROS production in cells [18,19]. In this study, the gene was up-regulated in the treated L-929 cells at 12 h, presuming that it may play a protective action to hypoxic cells and promote the restoration of actin cytoskeleton in the L-929 cells.…”

Section: Discussionmentioning

confidence: 68%

Genome-wide pathways analysis of nickel ion-induced differential genes expression in fibroblasts

Lü

Zhao

et al. 2010

Biomaterials

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Section: Discussionmentioning

confidence: 68%

Genome-wide pathways analysis of nickel ion-induced differential genes expression in fibroblasts

Lü

Zhao

et al. 2010

Biomaterials

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“…39 Our results stand in contrast to studies by Pula et al, who found that platelets treated with secramine A show a selective aggregation and adhesion defect in response to collagen. 40 This discrepancy is difficult to explain at present, but it might be related to limited specificity of the inhibitor. The increased secretion in Cdc42 Ϫ/Ϫ platelets stands in clear contrast to observations made in other cell types showing decreased exocytosis upon inhibition of Cdc42, including endothelial cells and mast cells.…”

Section: Discussionmentioning

confidence: 84%

Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

Pleines

Eckly

Elvers

et al. 2010

Blood

115

126

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Platelet activation at sites of vascular injury is crucial for hemostasis, but it may also cause myocardial infarction or stroke. Cytoskeletal reorganization is essential for platelet activation and secretion. The small GTPase Cdc42 has been implicated as an important mediator of filopodia formation and exocytosis in various cell types, but its exact function in platelets is not established. Here, we show that the megakaryocyte/platelet-specific loss of Cdc42 leads to mild thrombocytopenia and a small increase in platelet size in mice. Unexpectedly, Cdc42-deficient platelets were able to form normally shaped filopodia and spread fully on fibrinogen upon activation, whereas filopodia formation upon selective induction of GPIb signaling was reduced compared with wild-type platelets. Furthermore, Cdc42-deficient platelets showed enhanced secretion of ␣ granules, a higher adenosine diphosphate (ADP)/adenosine triphosphate (ATP) content, increased aggregation at low agonist concentrations, and enhanced aggregate formation on collagen under flow. In vivo, lack of Cdc42 resulted in faster occlusion of ferric chloride-injured arterioles. The life span of Cdc42-deficient platelets was markedly reduced, suggesting increased clearing of the cells under physiologic conditions. These data point to novel multiple functions of Cdc42 in the regulation of platelet activation, granule organization, degranulation, and a specific role in GPIb signaling. (Blood. 2010;115(16): 3364-3373) IntroductionAt sites of tissue trauma, platelets become activated and rapidly aggregate to form a plug that seals the wound and limits blood loss. On the other hand, platelet activation in pathologic situations can lead to thrombosis, causing myocardial infarction or stroke. Platelet activation by multiple signaling pathways leads to shape change, release of intracellularly stored granules, and spreading on immobilized ligands. Small GTPases of the Rho family, namely RhoA, Cdc42, and Rac1, are thought to play important roles in the cytoskeletal rearrangements occurring during platelet activation by facilitating the formation of stress fibers, filopodia and lamellipodia, respectively. 1 In platelets, signaling from G protein-coupled receptors, such as the thromboxane or thrombin receptors, as well as immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors (GPVI, CLEC-2) was shown to induce activation of Rho GTPases. 2,3 Cdc42 is a small (ϳ 23 kDa) protein that cycles between a GDP-bound inactive and a GTP-bound active state. 4 Cdc42 is an important mediator of filopodia formation in various cell types. According to the "convergent elongation model," active Cdc42 induces activation of Wiskott-Aldrich Syndrome protein (WASP). WASP subsequently activates the ARP2/3 complex, thereby increasing actin turnover and initiating the formation of parallel actin bundles. [5][6][7] Furthermore, Cdc42 can also bind to and activate IRSp53, which recruits the Ena/vasodilator-stimulated phosphoprotein (VASP) family protein Mena, thus promoting filopodi...

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“…Although it is not known whether it is the case with chondrocytes, activation of integrins is regulated by small GTPases in a variety of cells. To date, the involvement of H-Ras, R-Ras, Rap1a, Rap1b, and Cdc42 have been reported (42)(43)(44). Thus, we evaluated the expression of these GTPases in human articular chondrocytes, and found that all of them were expressed at substantial levels ( Figure 5B).…”

Section: ␣V␤5 Integrin Promotes Chondrocyte Dedifferentiationmentioning

confidence: 88%

αvβ5 Integrin promotes dedifferentiation of monolayer-cultured articular chondrocytes

Fukui¹,

Ikeda²,

Tanaka³

et al. 2011

Arthritis & Rheumatism

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Objective. When cultured in monolayers, articular chondrocytes undergo an obvious phenotypic change. Although the involvement of integrins has been suggested, the exact mechanisms of the change have not been determined. This study was undertaken to clarify the mechanisms underlying the loss of chondrocyte phenotype early after plating.Methods. Primary cultured human articular chondrocytes were used for the experiments. Involvement of respective integrins in the phenotypic change was investigated in RNA interference (RNAi) experiments. A signaling pathway involved in the change was identified in experiments using specific inhibitors and adenoviruses encoding mutated genes involved in the pathway. Adenoviruses carrying mutated GTPases were used to determine the involvement of small GTPases in the process.Results. In monolayer-cultured chondrocytes, suppression of ␣v or ␤5 integrin expression by RNAi inhibited morphologic changes in the cells and increased (or prevented a reduction in) the expression of various cartilage matrix genes. Consistent results were obtained in experiments using a blocking antibody and a synthetic inhibitor of ␣v␤5 integrin. The decrease in cartilage matrix gene expression in chondrocytes after plating was mediated by ERK signaling, which was promoted primarily by ␣v␤5 integrin. In articular chondrocytes, the affinity of ␣v␤5 integrin for ligands was regulated by the small GTPase R-Ras. R-Ras was gradually activated in monolayer-cultured chondrocytes after plating, which caused a gradual decline in cartilage matrix gene expression through enhanced ␣v␤5 integrin activation and the subsequent increase in ERK signaling.Conclusion. Our findings indicate that ␣v␤5 integrin may be involved in the change that occurs in monolayer-cultured chondrocytes after plating.

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Critical roles for the actin cytoskeleton and cdc42 in regulating platelet integrinα₂β₁

Cited by 29 publications

References 36 publications

Genome-wide pathways analysis of nickel ion-induced differential genes expression in fibroblasts

Genome-wide pathways analysis of nickel ion-induced differential genes expression in fibroblasts

Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

αvβ5 Integrin promotes dedifferentiation of monolayer-cultured articular chondrocytes

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