AKAP13, a RhoA GTPase-specific Guanine Exchange Factor, Is a Novel Regulator of TLR2 Signaling

Shibolet, Oren; Giallourakis, Cosmas; Rosenberg, Ian M.; Müller, Tobias; Xavier, Ramnik J.; Podolsky, Daniel K.

doi:10.1074/jbc.m704426200

Cited by 52 publications

(37 citation statements)

References 36 publications

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“…36 AKAP13, an anchoring protein, which has GEF activity, had its expression induced by TLR2 agonist Pam3cys, leading to activation of NF-kB and JNK and induction of pro-inflammatory cytokines. 37 It was shown that Ras signalling through TLR9 is in induction by CPG DNA in macrophages, and is involved in activation of ERK, JNK, and NF-kB, being required for secretion of TNF and nitric oxide. 38 We provide evidence that RasGEF1b is a TLRinducible gene with a potential function within inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

et al. 2010

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Guanine-nucleotide exchange factors (GEFs) stimulate the intrinsic GDP/GTP exchange activity of Ras and promote the formation of active Ras-GTP, which in turn controls diverse signalling networks important for the regulation of cell proliferation, survival, differentiation, vesicular trafficking, and gene expression. RasGEF1b is a GEF, whose expression is induced in macrophages on stimulation with toll-like receptor (TLR) agonists. Here, we showed that in vitro RasGEF1b expression by macrophages is mostly induced by TLR3 (poly I:C) and TLR4 (lipopolysaccharyde) through the MyD88-independent pathway. In vivo infection with the protozoan parasites Trypanosoma cruzi and Plasmodium chabaudi induced RasGEF1b in an MyD88-, TRIF-, and IFN-g-dependent manner. Ectopically expressed RasGEF1b was found, mostly, in the heavy membrane fraction of HEK 293T, and by confocal microscopy, it was found to be located at early endosomes. Computational modelling of the RasGEF1b-Ras interaction revealed that RasGEF1b interacts with the binding domain site of Ras, a critical region for interacting with GEFs involved in the activation of Ras-Raf-MEK-ERK pathway. More important, RasGEF1b was found to be closely associated with Ras in live cells and to trigger Ras activity. Altogether, these results indicate that on TLR activation, RasGEF1b may trigger Ras-like proteins and regulate specific biological activities described for this subtype of GTPases.

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Section: Discussionmentioning

confidence: 99%

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

et al. 2010

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“…In our analysis, a miRNA was considered as a hub when its P value was smaller than the probability of this rare event. This filtering criteria was supported by some previous studies (15,24). Then, we extracted miRNA clusters implicated by hubs, which include all miRNAs linked to the hubs directly.…”

Section: Extraction Of Mirna Clusters and Randomization Testsmentioning

confidence: 68%

Combination of microRNA expression profiling with genome-wide SNP genotyping to construct a coronary artery disease-related miRNA-miRNA synergistic network

Hua

Xia

Zhou

et al. 2014

BST

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“…33 It is also known that the activation of RhoA is important for the translocation of nuclear factor B to the nucleus after stimulation of the toll-like receptor 2. 37 Interestingly, the partial inhibition of lung neutrophil activity by CGX0287 did not result in more lung damage 4 h after P. aeruginosa instillation. A possible explanation is that, despite the fact neutrophils are critical for the long-term clearance of bacteria from the lung, a large accumulation of these immune cells into the airspace can result in tissue damage caused by the exuberant inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of the Small GTPase RhoA in the Development of Pulmonary Edema Induced by Pseudomonas aeruginosa in Mice

Carlès

Lafargue

Goolaerts³

et al. 2010

Anesthesiology

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Background:Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe pneumonia in critically ill patients. We have reported previously that P. aeruginosa exotoxins S and T mediate in vitro the increase in protein permeability across lung endothelial cell monolayers via a RhoA-dependent mechanism. However, whether inhibition of RhoA would significantly attenuate P. aeruginosa-mediated lung injury in mice is unknown. Methods: P. aeruginosa-induced paracellular protein permeability was measured across bovine lung endothelial and rat alveolar epithelial type II cell monolayers with 125 I-albumin. Some cell monolayers were pretreated with RhoA inhibitor CGX0287 1 h before P. aeruginosa exposure. At 4 h after exposure, lung endothelial and epithelial permeability, bacterial counts, bronchoalveolar lavage fluid levels of keratinocyte-derived chemokine, myeloperoxidase activity, and alveolar fluid clearance were measured. Some mice were treated intraperitoneally with CGX0287 1 h before or after airspace instillation of P. aeruginosa. Results: RhoA inhibition attenuated in vitro P. aeruginosamediated increase in lung endothelial and epithelial permeability to protein and in vivo the development of pulmonary edema and inhibition of alveolar fluid clearance associated with P. aeruginosa pneumonia. Furthermore, RhoA inhibition decreased the systemic dissemination of P. aeruginosa and neutrophil activity in the lung tissue observed after airspace instillation of these bacteria. Conclusions: The small GTPase RhoA plays a critical role in mediating lung injury associated with P. aeruginosa pneumonia in mice. Thus, transient blockade of RhoA could attenuate lung damage caused by P. aeruginosa in critically ill patients.

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AKAP13, a RhoA GTPase-specific Guanine Exchange Factor, Is a Novel Regulator of TLR2 Signaling

Cited by 52 publications

References 36 publications

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

Combination of microRNA expression profiling with genome-wide SNP genotyping to construct a coronary artery disease-related miRNA-miRNA synergistic network

Critical Role of the Small GTPase RhoA in the Development of Pulmonary Edema Induced by Pseudomonas aeruginosa in Mice

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