β1 Integrin Ligation Stimulates Tyrosine Phosphorylation of Phospholipase Cγ1 and Elevates Intracellular Ca2+in Pancreatic Acinar Cells

Wrenn, Robert W.; Creazzo, Tony L.; Herman, Lee E.

doi:10.1006/bbrc.1996.1443

Cited by 20 publications

(10 citation statements)

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“…These data indicate that fibrinogen stimulation triggers functional activation of PLC␥2 downstream of the platelet integrin ␣ IIb ␤ 3 . Activation of PLC isoforms and its importance in integrin-mediated Ca 2ϩ signaling is a well established phenomenon and has been observed in various cells expressing different integrins (32)(33)(34)(35)(36) including platelets activated by the ␣ 2 ␤ 1 -specific peptide GFOGER (37).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading

Wonerow

Pearce

Vaux

et al. 2003

Journal of Biological Chemistry

123

155

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The interaction of fibrinogen with the integrin ␣ IIb ␤ 3 plays a crucial role in platelet adhesion and platelet activation leading to the generation of intracellular signals that nucleate the reorganization of the cytoskeleton. Presently, we have only a limited understanding of the signaling cascades and effector proteins through which changes in the cytoskeletal architecture are mediated. The present study identifies phospholipase C␥2 (PLC␥2) as an important target of the Src-dependent signaling cascade regulated by ␣ IIb ␤ 3 . Real time phasecontrast microscopy is used to show that formation of filopodia and lamellapodia in murine platelets on a fibrinogen surface is dramatically inhibited in the absence of PLC␥2. Significantly, the formation of these structures is mediated by Ca 2؉ elevation and activation of protein kinase C, both directly regulated by PLC activity. With the involvement of Syk, SLP-76, and Btk, ␣ IIb ␤ 3 -induced PLC␥2 activation partly overlaps with the pathway used by the collagen receptor glycoprotein VI. Important differences, however, exist between the two signaling cascades in that activation of PLC␥2 by ␣ IIb ␤ 3 is unaltered in murine platelets, which lack the FcR ␥-chain or the adaptor LAT, but is abolished in the presence of cytochalasin D. Therefore, PLC␥2 plays not only a crucial role in activation of ␣ IIb ␤ 3 by collagen receptors but also in ␣ IIb ␤ 3 -mediated responses.The integrin ␣ IIb ␤ 3 mediates platelet aggregation in cell suspensions and supports adhesion to fibrinogen and von Willebrand factor (vWf) 1 -coated surfaces. On resting platelets, the integrin is in a low affinity conformation that does not support binding to either adhesion molecule at their normal plasma concentrations. An increase in affinity of ␣ IIb ␤ 3 , leading to fibrinogen and vWf binding, is mediated by inside-out signals from G protein-coupled and tyrosine kinase-linked agonists, and thereby promotes aggregation. In addition, binding to ␣ IIb ␤ 3 induces outside-in signals that lead to reorganization of the cytoskeleton and synergize with other agonists to mediate activation. The central role of the integrin ␣ IIb ␤ 3 in thrombosis and hemostasis is highlighted by the severe bleeding disorders in patients with Glanzmann thrombasthenia, which lack functional integrin.One of the earlier events to occur following ligation of ␣ IIb ␤ 3 is the activation of the tyrosine kinase Syk via one or more Src kinases (1, 2). This leads to tyrosine phosphorylation of the adaptor molecule SLP-76, which is constitutively associated with a second adaptor SLAP-130 (3, 4), also known as Fynbinding protein or adhesion-and degranulation-promoting adapter protein (5, 6). Together with proteins of the Vav GTPase exchange family, the adapter Nck, and the actin-binding protein VASP, this cascade has been shown to lead to activation of phosphoinositol 3-kinase and phosphorylation of FAK, and subsequent reorganization of the cytoskeleton in ␣ IIb ␤ 3 -transfected Chinese hamster ovary cells (7-9). Evidence that this casc...

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Section: Discussionmentioning

confidence: 99%

A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading

Wonerow

Pearce

Vaux

et al. 2003

Journal of Biological Chemistry

123

155

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“…However, PS1-⌬E9 mutants failed to stabilize cadherin-catenin complexes and stimulate cell-cell adhesion (39). Interestingly, the ␥ isoform of PLC can be activated by integrins (40,41), another component of the cell to cell adhesion complex, and integrin functions in cell adhesion and signaling have been shown to be regulated by the Ca 2ϩ -dependent enzyme calpain (42,43). We showed that, compared with NT and PS1-WT cells, the PS1-⌬E9 transfectants gave a relative increase in levels of the calpain-generated N-terminal fragment (100 kDa) over fulllength (150 kDa) PLC-␤1.…”

Section: Discussionmentioning

confidence: 99%

The Presenilin 1 ΔE9 Mutation Gives Enhanced Basal Phospholipase C Activity and a Resultant Increase in Intracellular Calcium Concentrations

Cedazo-Mı́nguez

Popescu

Ankarcrona

et al. 2002

Journal of Biological Chemistry

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We studied effects of the familial Alzheimer's disease presenilin 1 (PS1) exon 9 deletion (PS1-⌬E9) mutation on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular ATPase inhibitor cyclopiazonic acid. Immunostaining experiments revealed that for all the cell types PS1 is present at the plasma membrane and colocalizes with N-cadherin, a component of the cell-cell adhesion complex. Immunoblotting of cell extracts for PLC-␤1 showed that, compared with NT and PS1-WT cells, the PS1-⌬E9 transfectants gave a relative increase in levels of the calpain generated N-terminal fragment (100 kDa) over full-length (150 kDa) PLC-␤1. Our results suggest that the PS1-⌬E9 mutation causes upstream changes in PI signaling with enhanced basal PLC activity as a primary effect that leads to a higher [Ca 2؉ ] i . This may provide a novel mechanism by which the PS1-⌬E9 mutation sensitizes cells to apoptotic stimuli and enhanced amyloid ␤ generation.Mutations in the presenilin 1 (PS1) 1 gene on chromosome 14 account for a large proportion of the early onset familial cases of Alzheimer's disease (FAD) (1). Two pathogenic mechanisms have been proposed by which PS1 mutations cause FAD. One mechanism involves altered proteolytic processing of the amyloid precursor protein (APP). Fibroblasts from PS1 mutation bearing individuals, brains from mice overexpressing mutant PS1, as well as cells transfected with FAD-linked PS1 variants, all produce a greater proportion of longer, more fibrillogenic forms of ␤-amyloid (A␤) (2-4). Several recent studies have shown that PS1 plays an important role in regulating the ␥-secretase cleavage of APP (5-7), and it has been hypothesized that PS could in fact be the ␥-secretase enzyme (8).A second mechanism proposes that PS1 mutations make cells more vulnerable to undergo death by apoptosis. Guo et al. (9) showed that the PS1-L286V mutation increases the vulnerability of PC12 cells to apoptosis induced by A␤ (9) and nerve growth factor withdrawal (10). The pro-apoptotic effects of PS1 have been shown to involve increases in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and peroxide levels under conditions of oxidative and excitotoxic stress (9, 10). Hippocampal neurons from L286V PS1 mutant knock-in mice are more vulnerable to excitotoxicity associated with increased [Ca 2ϩ ] i levels (10). These data are in accordance with older reports showing that bradykinin-stimulated fibroblasts from FAD patients have higher [Ca 2ϩ ] i than fibroblasts from age-matched controls (11,12). Dysregulation of [Ca 2ϩ ] i may be of importance in the pathogenesis of AD, because it has also been shown to contribute to enhanced A␤ generation (13) and tau protein hyperphosphorylation (14).A large proportion of Ca 2ϩ mobilization and regulation in neurons can be attributable to cholinergic neurotransmission (15). Activation of phospholipase C (PLC) results in hydrolysis of phosphoinositides (PI) to give formation of the second messengers inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol. A...

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“…PLC-γ1 is known to be involved in the secretory function of the acinar cells (Wrenn et al, 1996). Its location of expression suggests the PLC-γ1's role in mediating transduction events underlying trophic signals inside the insulinsecreting β cells.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical localization of eight phospholipase C isozymes in pancreatic islets of the mouse

Kim¹,

Jun²,

Jeong³

et al. 2001

Exp Mol Med

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The possible involvement of phospholipase C (PLC) in the regulation of insulin secretion is not clearly understood and neither its isozymes expressed nor cellular localization in the pancreatic islets is known. By using specific monoclonal antibodies, we have investigated the expression and localization of eight different PLC isozymes, β1, β2, β3, β4, γ1, γ2, δ1, and δ2, in the pancreatic islets of adult mice. Immunohistochemical analysis carried out on paraffin embedded sections showed a distinct pattern of expression for each of the PLC isozymes. In the central part of the islets containing β cells, a high level of β4 and moderate levels of β3 and γ1 were expressed, whereas PLC-β1 and −γ1 were abundantly expressed in the exocrine pancreas. These results demonstrated the heterogeneity in expression of the phospholipase C isozymes in pancreatic islets. It is conceivable that these isozymes are coupled to different receptors and perform selective tasks in the regulation of insulin secretion for glucose homeostasis.

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β1 Integrin Ligation Stimulates Tyrosine Phosphorylation of Phospholipase Cγ1 and Elevates Intracellular Ca2+in Pancreatic Acinar Cells

Cited by 20 publications

References 0 publications

A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading

A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading

The Presenilin 1 ΔE9 Mutation Gives Enhanced Basal Phospholipase C Activity and a Resultant Increase in Intracellular Calcium Concentrations

Immunohistochemical localization of eight phospholipase C isozymes in pancreatic islets of the mouse

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