Phospholipase Cγ2 contributes to stable thrombus formation on VWF

Rathore, Vipul; Wang, Demin; Newman, Debra K.; Newman, Peter J.

doi:10.1016/j.febslet.2004.07.048

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…However, the PLC-selective basis of these pharmacological inhibitors is unclear. Published data showing that Plcg2 -/-platelets have a spreading defect following adhesion to collagen, fibrinogen or vonWillebrand factor (Asselin et al, 1997;Goncalves et al, 2003;Inoue et al, 2003;Wonerow et al, 2003;Rathore et al, 2004) concurs with our data. In contrast to our data, Plcg2 -/-platelets do not show deficits in cell adhesion.…”

Section: Discussionsupporting

confidence: 81%

Integrin-dependent PLC-γ1 phosphorylation mediates fibronectin-dependent adhesion

Tvorogov

Wang

Zent

et al. 2005

Journal of Cell Science

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IntroductionThe hydrolysis of membrane phospholipids is one of the earliest cellular responses to many extracellular stimuli. Phospholipases C (PLCs), a crucial group of enzymes in signal transduction, catalyses the hydrolysis of phosphatidylinositol-4,5-bisphosphate to inositol-1,4,5-trisphosphate and diacylglycerol, two molecules that regulate the mobilization of intracellular Ca 2+ and protein-kinase-C activation, respectively (Berridge and Irvine, 1984). Phospholipase Cγ1 (PLC-γ1) is a member of the phosphoinositide-specific PLC family and is recognized for its role in growth-factor-dependent signal transduction .All PLC isozymes contain X and Y domains that fold together to form the catalytic site. The unique feature of the PLC-γ subfamily, which includes two isozymes, is the presence of a large linker between the X and Y domains that contains two SH2 domains, one SH3 domain and two sites of tyrosine phosphorylation . The SH2 domains mediate the association of PLC-γ with tyrosine-phosphorylated proteins, especially activated growth-factor-receptor tyrosine kinases. Nearly all growth factors induce the tyrosine phosphorylation and activation of PLC-γ1 and thereby stimulate phosphatidylinositol-4,5-bisphosphate turnover. SH2-domain-mediated binding of PLC-γ1 to activated receptors leads to the tyrosine phosphorylation of PLC-γ1 at three tyrosine residues: Tyr771, Tyr783 and Tyr1254. Biochemical studies have revealed that tyrosine phosphorylation activates PLC-γ1 enzyme activity (Nishibe et al., 1990) and site-directed mutagenesis (Kim et al., 1991) implicates Tyr783 as essential for PLC-γ1 activation by growth factors.Integrins are cell-surface receptors that mediate interactions between cells and the extracellular matrix (ECM) and have a crucial role in cellular functions such as cell adhesion, migration, proliferation and apoptosis. Integrins are heterodimeric molecules comprising an α and a β subunit, which combine in a restricted manner to form various dimers, each of which exhibits different ligand-binding properties (Hynes, 2002;Plow et al., 2000). The extracellular domains of integrin subunits are large and constitute the ligand-binding domain(s) of these receptors, whereas the short cytoplasmic tails play a crucial role in the promotion of cell anchorage. The cytoplasmic domains interact with cytoskeletal proteins to facilitate the connection of integrins to the cytoskeleton (van der Flier and Sonnenberg, 2001). In addition, the cytoplasmic domains also recruit cytoplasmic tyrosine kinases such as focal-adhesion kinase (FAK), integrin-linked kinase and Src-family kinases, to propagate signals from the engaged 601 Although integrin engagement initiates signaling events such as focal-adhesion kinase (FAK) and Src kinase activation, the role of phosphoinositide turnover in cell adhesion is less clear. To assess PLC-γ1 function in this process, Plcg1 -/-fibroblasts (Null) were compared with the same fibroblasts in which PLC-γ1 was re-expressed (Null+). Following plating on fibronectin, Null cells displaye...

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Section: Discussionsupporting

confidence: 81%

Integrin-dependent PLC-γ1 phosphorylation mediates fibronectin-dependent adhesion

Tvorogov

Wang

Zent

et al. 2005

Journal of Cell Science

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“…The tyrosine kinase Syk and the effector enzyme PLC␥2 play critical roles in platelet spreading downstream of integrins ␣ IIb ␤ 3 and ␣ 2 ␤ 1 . [5][6][7]20,21 As shown in Figure 2, analysis by DIC microscopy revealed that formation of lamellipodia in mouse platelets on laminin was almost completely inhibited in the absence of Syk or PLC␥2, although there was no effect on the level of adhesion. Interestingly, the degree of inhibition of spreading was more marked in the absence of Syk relative to the absence of PLC␥2.…”

Section: Dissection Of Signaling Events In Platelet Spreading On Lamininmentioning

confidence: 99%

Laminin stimulates spreading of platelets through integrin α6β1–dependent activation of GPVI

Ito

Suzuki‐Inoue

McCarty

et al. 2006

Blood

175

135

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The extracellular matrix protein, laminin, supports platelet adhesion through binding to integrin ␣ 6 ␤ 1 In the present study, we demonstrate that human laminin, purified from placenta, also stimulates formation of filopodia and lamellipodia in human and mouse platelets through a pathway that is dependent on ␣ 6 ␤ 1 and the collagen receptor GPVI. The integrin ␣ 6 ␤ 1 is essential for adhesion to laminin, as demonstrated using an ␣ 6 -blocking antibody, whereas GPVI is dispensable for this response, as shown using "knockout" mouse platelets. On the other hand, lamellipodia formation on laminin is completely inhibited in the absence of GPVI, although filopodia formation remains and is presumably mediated via ␣ 6 ␤ 1 Lamellipodia and filopodia formation are inhibited in Syk-deficient platelets, demonstrating a key role for the kinase in signaling downstream of GPVI and integrin ␣ 6 ␤ 1 GPVI was confirmed as a receptor for laminin using surface plasmon resonance spectroscopy and by demonstration of lamellipodia formation on laminin in the presence of collagenase. These results identify GPVI as a novel receptor for laminin and support a model in which integrin ␣ 6 ␤ 1 brings laminin to GPVI, which in turn mediates lamellipodia formation. We speculate that laminin contributes to platelet spreading in vivo through a direct interaction with GPVI. IntroductionPlatelets play a critical role in the hemostatic process through a combination of adhesion, activation, and aggregation events that lead to formation of a platelet plug and occlusion of the site of damage. Our current understanding of this process highlights a critical role for the interaction of von Willebrand factor (VWF) with the platelet surface receptor, GPIb-IX-V, in mediating platelet tethering at arterial rates of flow. 1,2 This is followed by platelet activation mediated by binding of collagen to the immunoglobulin receptor, GPVI, leading to inside-out stimulation of the integrins, ␣ 2 ␤ 1 and ␣ IIb ␤ 3 . 3 The 2 integrins bind to their respective ligands, collagen and VWF, mediating stable adhesion. Platelet adhesion is further strengthened by integrin-dependent platelet spreading. [4][5][6][7] Platelet aggregation is mediated through binding of fibrinogen to integrin ␣ IIb ␤ 3 in a process dependent on release of the secondary mediators, ADP and thromboxanes. [8][9][10] The contribution of other extracellular matrix proteins to the hemostatic process is unclear. Recently, however, Nieswandt's group 11 has highlighted a possible role for the 2 ␤ 1 -integrins, ␣ 5 ␤ 1 and ␣ 6 ␤ 1 , which are receptors for fibronectin and laminin, respectively, in supporting adhesion in vivo in concert with integrins ␣ 2 ␤ 1 and ␣ IIb ␤ 3 . This was achieved by comparing platelet adhesion and aggregate formation in vivo using fluorescent intravital microscopy in mice deficient in ␣ 2 and ␤ 1 integrin subunits and in the presence of ␣ IIb ␤ 3 blockade. 11 This study therefore illustrates that laminin, fibronectin, and other ligands for ␣ 5 ␤ 1 and ␣ 6 ␤ 1 may contribute to...

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“…Thus, collagen binding to the integrin ␣2␤1 uses both the ITAM-bearing GPVI/FcR␥ chain [59][60][61] as well as PLC␥2 17 to transmit activation signals, as does the integrin ␣6␤1 when platelets encounter the extracellular matrix protein laminin. 62,63 Similarly, interaction of von Willebrand factor with the platelet GPIb complex results in activation of Src family kinases, Syk, and PLC␥2, 64-67 and we and others have shown a critical role for PLC␥2 in supporting platelet spreading 66,68 and thrombus formation 68 on immobilized VWF under conditions of flow. Unlike collagen, laminin, or fibrinogen binding-induced activation, however, VWF-induced platelet activation does not appear to require Fc␥RIIa or the FcR␥ chain to transmit adhesiondependent signals, 66,69 although their ability to serve as costimulatory signal amplification molecules, when present, has not been ruled out.…”

Section: Outside-inmentioning

confidence: 99%

Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets

Boylan

Gao

Rathore

et al. 2008

Blood

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155

148

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Phospholipase Cγ2 contributes to stable thrombus formation on VWF

Cited by 16 publications

References 27 publications

Integrin-dependent PLC-γ1 phosphorylation mediates fibronectin-dependent adhesion

Integrin-dependent PLC-γ1 phosphorylation mediates fibronectin-dependent adhesion

Laminin stimulates spreading of platelets through integrin α6β1–dependent activation of GPVI

Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets

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