Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

Bekay, Rajaa El; Álba, Gonzalo; Reyes, Marı́a Edith; Chacón, Pedro; Vega, Antonio Pereira; Martı́n-Nieto, José; Jiménez, Juan; Ramos, Eladio; Oliván, J; Pintado, Elı́zabeth; Sobrino, Francisco

doi:10.1677/jme-07-0074

Cited by 19 publications

(14 citation statements)

References 64 publications

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“…Similarly, calcineurin has been shown to regulate activation of the Rac2 isoform in human neutrophils. 43 Our further results with the calcineurin inhibitor point to a critical role of Rac1/class II PAKs activation in cofilin dephosphorylation and secretion (Table 2). In support, independent overexpression of PAK1 and ADF in chromaffin cells showed similar enhancement of agonist-induced secretion from these cells.…”

Section: Discussionmentioning

confidence: 73%

Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets

Pandey

Goyal

Dwivedi

et al. 2009

Blood

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In platelets stimulated by thrombin to secrete and aggregate, cofilin is rapidly dephosphorylated leading to its activation. Cofilin by severing existing actin filaments and stimulating F-actin polymerization on newly created barbed ends dynamizes the actin cytoskeleton. We previously found that cofilin dephosphorylation is Ca 2؉ -dependent and occurs upstream of degranulation in stimulated platelets. We report now in thrombinstimulated platelets that Rac1 and class II PAKs (PAK4/5/6) were rapidly (within 5 seconds) activated, whereas PAK1/2 (class I PAKs) phosphorylation was slower. The Rac1-specific inhibitor NSC23766 blocked phosphorylation of class II PAKs, but not PAK1/2. Moreover, inhibition of the Ca 2؉ /calmodulindependent phosphatase calcineurin inhibited Rac1 activation and class II PAKs phosphorylation. Prevention of Rac1 activation by calcineurin inhibition or NSC23766 also blocked cofilin dephosphorylation and platelet granule secretion indicating that a calcineurin/Rac1/ class II PAKs pathway regulates cofilin dephosphorylation leading to secretion.We further found that PI3-kinases were activated downstream of Rac1, but were not involved in regulating cofilin dephosphorylation and secretion in thrombinstimulated platelets. Our study unravels a Ca 2؉ -dependent pathway of secretion in stimulated platelets as a signaling pathway linking Rac1 activation to actin dynamics: calcineurin3Rac13class II PAKs3cofilin activation. We further demonstrate that this pathway is separate and independent of the protein kinase C (PKC) pathway mediating secretion. (Blood. 2009;114:415-424)

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Section: Discussionmentioning

confidence: 73%

Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets

Pandey

Goyal

Dwivedi

et al. 2009

Blood

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“…Activation of p38 MAPK is required for cytoskeleton re-arrangement and subsequent autophagy (Park et al, 2008; Tang et al, 2008). The small GTPase Rac has been implicated in membrane ruffling and phagocytosis (Ridley et al, 1992; Cox et al, 1997), and its activation by GTP-loading and cytosol to membrane translocation is regulated by p38 activity (El Bekay et al, 2007; Zuluaga et al, 2007; Osada et al, 2009). To assess whether fAβ-stimulated p38 activation via the fAβ receptor complex modulated phagocytosis, we treated microglia with the p38 inhibitor SB203580 prior to fAβ stimulation.…”

Section: Resultsmentioning

confidence: 99%

CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation

Reed-Geaghan¹,

Savage²,

Hise³

et al. 2009

J. Neurosci.

509

415

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Microglia are the brain's tissue macrophages and are found in an activated state surrounding ␤-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar ␤-amyloid (fA␤) through an ensemble of surface receptors composed of the ␣ 6 ␤ 1 integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of A␤ requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fA␤ is reliant upon CD14, which act together with TLR4 and TLR2 to bind fA␤ and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fA␤-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fA␤-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IB␣ following fA␤. These data indicate these innate immune receptors function as members of the microglial fA␤ receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.

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“…In agreement with cell and animal studies as well as clinical trials they also confirm the deleterious effects of Ang II which acts both in a chronic fashion by increasing the expression of NAD(P)Hoxidase and iNOS and in acute manner by activating them thereby leading to increased nitrative stress. The activation mechanisms of iNOS are obviously very complex and involves interactions with multiple proteins [62] including Rac2 [63], Src [64] and Gα subunits [65] which can be triggered by Ang II AT 1 receptors. The recent reports by Skidgel's group [59], [60] suggesting the involvement of ERK are supported by our observations and further strengthen the role of this enzyme in G-protein coupled receptor signaling pathways such as Ang II and kinins.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Inhibits Insulin-Stimulated GLUT4 Translocation and Akt Activation through Tyrosine Nitration-Dependent Mechanisms

et al. 2010

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Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O2 .−-dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser473 and Thr308 as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3α phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr156/139, close to their active site Asp166/149, in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein nitration as a major mechanism in the regulation of Ang II and insulin signaling pathways and more particularly as a key regulator of protein kinase activity.

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Rac2 GTPase activation by angiotensin II is modulated by Ca2+/calcineurin and mitogen-activated protein kinases in human neutrophils

Cited by 19 publications

References 64 publications

Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets

Unraveling a novel Rac1-mediated signaling pathway that regulates cofilin dephosphorylation and secretion in thrombin-stimulated platelets

CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation

Angiotensin II Inhibits Insulin-Stimulated GLUT4 Translocation and Akt Activation through Tyrosine Nitration-Dependent Mechanisms

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