Rac and Phosphatidylinositol 3-Kinase Regulate the Protein Kinase B in FcεRI Signaling in RBL 2H3 Mast Cells

Djouder, Nabil; Schmidt, Gudula; Frings, M.; Cavalié, Adolfo; Thelen, Marcus; Aktories, Klaus

doi:10.4049/jimmunol.166.3.1627

Cited by 41 publications

(41 citation statements)

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“…Consistently, antioxidants and DPI diminish Akt phosphorylation in VSMCs in response to angiotensin II, another potent activator of the NADPH oxidase, 28 further supporting the idea that Akt is specifically activated via the NADPH oxidase. Similarly, in rat basophilic leukemic cells, C difficile toxin B has been shown to decrease phosphorylation of Akt but not of ERK1/2 in response to Fc⑀ receptor stimulation, 29 and in murine hematopoietic BaF3 cells, Rac was essentially involved in the activation of Akt and p38 MAP kinase. 30 Because PI 3-kinase inhibitors attenuate TF mRNA expression and Akt phosphorylation in response to thrombin, the NADPH oxidase-mediated activation of the PI 3-kinase/Akt pathway may thus provide a novel mechanism contributing to thrombin-induced TF expression and surface procoagulant activity.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells

et al. 2002

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Background-Tissue factor (TF) initiates the extrinsic coagulation cascade leading to thrombin formation. Thrombin induces TF mRNA in vascular smooth muscle cells (VSMCs), thereby contributing to the prolonged procoagulant activity and enhanced thrombogenicity at sites of vascular injury. However, the signaling mechanisms mediating this thrombogenic cycle are unclear. Characteristically, vascular injury promotes the generation of reactive oxygen species (ROS). Because ROS exert signaling functions, we investigated whether the NADPH oxidase, an important source of ROS in VSMCs, contributes to upregulation of TF by thrombin. Methods and Results-Thrombin not only stimulated TF mRNA expression, but also TF-dependent surface procoagulant activity in cultured human VSMCs. This response was attenuated by antioxidants; the flavin inhibitor diphenyleneiodonium, Clostridium difficile toxin B, which inhibits Rho GTPases, p22phox antisense oligonucleotides, or the dominant-negative RacT17N mutant. Inhibitors of p38 MAP kinase and phosphatidylinositol (PI) 3-kinase also prevented thrombin-stimulated TF mRNA expression. Furthermore, thrombin stimulated the phosphorylation of the PI 3-kinase target protein kinase B/Akt in a redox-sensitive and NADPH oxidase-dependent manner. Conclusion-These findings indicate that the NADPH oxidase is essentially involved in the redox-sensitive induction of TF mRNA expression and surface procoagulant activity by thrombin. This response is mediated by NADPH oxidase-dependent activation of p38 MAP kinase and the PI 3-kinase/protein kinase B/Akt pathway. Given that active TF promotes thrombin formation, the NADPH oxidase may play a crucial role in perpetuating the thrombogenic cycle in the injured vessel wall.

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Section: Discussionmentioning

confidence: 99%

NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells

et al. 2002

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“…Previous studies have shown that the activation of Rho GTPases is PI3K-independent in RBL-2H3 cells [24]. PLCc was found to directly bind Cdc42 in vitro in these cells [21], suggesting that PLCc could be a downstream effector of Rho GTPases in response to antigen stimulation.…”

Section: Introductionmentioning

confidence: 99%

“…However, it has been reported that Rac activation in response to antigen stimulation in mast cells is PI3K-independent [24]. This led us to examine other effectors in the degranulation pathway with regard to Rac and Cdc42 regulation.…”

Section: Plcc Inhibition Increases the Activation Of Rac And Cdc42mentioning

confidence: 99%

“…Patch clamp studies in the same system showed that Rac/ Cdc42 are involved in calcium mobilization, in part through the regulation of calcium release-activated calcium channels [23]. Rac/Cdc42 also play a positive role in the activation of PLCc, the generation of IP 3 , and the aggregation of the IP 3 receptor in response to the engagement of the FceRI [21,24].…”

Section: Introductionmentioning

confidence: 99%

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Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

El‐Sibai

Backer

2006

Eur J Immunol

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The Rho GTPases Rac and Cdc42 play a central role in the regulation of secretory and cytoskeletal responses in antigen-stimulated mast cells. In this study, we examine the kinetics and mechanism of Rac and Cdc42 activation in the rat basophilic leukemia RBL-2H3 cells. The activation kinetics of both Rac and Cdc42 show a biphasic profile, consisting of an early transient peak at 1 min and a late sustained activation phase at 20-40 min. The inhibition of phospholipase C (PLC)c causes a twofold increase in Rac and Cdc42 activation that coincides with a dramatic production of atypical filopodialike structures. Inhibition of protein kinase C using bisindolylmaleimide mimics the effect of PLCc inhibition on Rac activation, but not on Cdc42 activation. In contrast, depletion of intracellular calcium leads to a complete inhibition of the early activation peak of both Rac and Cdc42, without significant effects on the late sustained activation. These data suggest that PLCc is involved in a negative feedback loop that leads to the inhibition of Rac and Cdc42. They also suggest that the presence of intracellular calcium is a prerequisite for both Rac and Cdc42 activation. IntroductionMast cells participate in the pathogenesis of immediate hypersensitivity and allergic reactions in humans [1]. Moreover, mast cells are important contributors to airway hyper-responsiveness that occurs in asthmatic inflammation [2]. In response to allergens and other exogenous stimuli, mast cells accumulate in the airway smooth muscle and in the bronchial intraepithelial layer [3]. The activation of mast cells, through the crosslinking of the FceRI, leads to the release of pre-formed early-phase inflammatory mediators and vasoactive substances from granules. It also leads to the in situ production of cytokines and bioactive lipids that contribute to the late-phase manifestation of the asthmatic reaction [4].Aggregation of FceRI on the surface of mast cells in response to multivalent ligand binding initiates a cascade of downstream signaling effectors that leads to degranulation [5]. These include phosphatidylinositol 3-kinase (PI3K), the guanine nucleotide exchange factor Vav, and phospholipase C (PLC)c1 [6]. The early activation of PLCc1 results in the generation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. These two second messengers lead to increases in cytoplasmic calcium and activation of calcium/diacylglycerol-regulated isoforms of protein kinase C (PKC) which culminate in granule margination and exocytosis [7]. PI3K plays an important regulatory role as an upstream activator of PLCc1, as well as a regulator of calcium flux during mast cell degranulation [8][9][10][11][12][13].Members of the Rho family of small GTPases also regulate signaling events in mast cells [14][15][16]. In the rat basophilic leukemia (RBL-2H3) cells, Rac and Cdc42 have been implicated in the control of the FceRImediated phagocytosis and the regulation of migration, In conjunction with the secretory response, antigenstimulated mast cells undergo drama...

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“…Le domaine PH, dont la fonction normale est de se lier à certains phospholipides membranaires [9, 10], pourrait jouer un rôle potentialisateur de l'activité des protéines Vav. Cependant, l'activation de Vav par liaison aux phospho-inositides membranaires n'est pas clairement établie et certaines publications récentes définissent une hiérarchie dans laquelle la voie PI-3K est activée en aval ou en parallèle des protéines Vav et de leurs substrats [11,12]. À côté de cette régulation de l'activité catalytique d'échange, la région carboxy-terminale comprenant les domaines SH3-SH2-SH3 joue un rôle adaptateur essentiel en recrutant des molécules de signalisation participant à la régulation de l'activité de Vav.…”

Section: Régulation De L'activité Des Protéines Vavunclassified

Les lymphocytes : comment ça « Vav »?

Charvet

Deckert

2003

Med Sci (Paris)

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Rac and Phosphatidylinositol 3-Kinase Regulate the Protein Kinase B in FcεRI Signaling in RBL 2H3 Mast Cells

Cited by 41 publications

References 64 publications

NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells

NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells

Phospholipase Cγ negatively regulates Rac/Cdc42 activation in antigen‐stimulated mast cells

Les lymphocytes : comment ça « Vav »?

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