Rac1 and Rac2 control distinct events during antigen-stimulated mast cell exocytosis

Baier, Alicia; Ndoh, Vivian N. E.; Lacy, Paige; Eitzen, Gary

doi:10.1189/jlb.0513281

Cited by 20 publications

(23 citation statements)

References 64 publications

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“…Our findings of significant alterations (rounding) in cells exposed to inhibitors of protein prenylation (simvastatin) suggest that they induce significant defects in the actin cytoskeleton leading to alterations in cell morphology (current studies) and inhibition of GSIS as shown earlier [13, 30]. It should be noted however that studies by Baier et al [31] and Shutes and coworkers [20] demonstrated significant inhibitory effects of EHT 1864 on membrane ruffling in mast cells and lamellipodia formation in U87 MG glioblastoma cells. The observed differences between these studies and our current investigations may, in part, be due to differences in cell types studied and the concentrations of EHT 1864 employed (20 μM in mast cells and 5 μM in glioblastoma cells) [20, 31].…”

Section: Discussionsupporting

confidence: 66%

“…It should be noted however that studies by Baier et al [31] and Shutes and coworkers [20] demonstrated significant inhibitory effects of EHT 1864 on membrane ruffling in mast cells and lamellipodia formation in U87 MG glioblastoma cells. The observed differences between these studies and our current investigations may, in part, be due to differences in cell types studied and the concentrations of EHT 1864 employed (20 μM in mast cells and 5 μM in glioblastoma cells) [20, 31]. …”

Section: Discussionmentioning

confidence: 99%

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EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic β-cells

Sidarala

Veluthakal

Syeda

et al. 2015

Cellular Signalling

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Glucose-stimulated insulin secretion (GSIS) in the pancreatic β-cells entails a variety of signaling mechanisms including activation of small GTP-binding proteins (G-proteins). Previous studies from our laboratory in human islets, rodent islets and clonal β-cells have demonstrated that G-proteins (e.g., Arf6, Cdc42 and Rac1) play novel roles in cytoskeletal remodeling, which is a critical step in the trafficking of insulin-laden secretory granules for fusion with plasma membrane and release of insulin. To further understand regulatory roles of Rac1 in GSIS, we utilized, herein, EHT 1864, a small molecule inhibitor, which attenuates Rac1 activation by retaining the G-protein in an inert/inactive state, thereby preventing activation of its downstream effector proteins. We demonstrate that EHT 1864 markedly attenuated GSIS in INS-1 832/13 cells. In addition, EHT 1864 significantly reduced glucose-induced activation and membrane targeting of Rac1 in INS-1 832/13 cells. This Rac1 inhibitor also suppressed glucose-induced activation of ERK1/2 and p53, but not Akt. Lastly, unlike the inhibitors of protein prenylation (simvastatin), EHT 1864 did not exert any significant effects on cell morphology (cell rounding) under the conditions it attenuated Rac1-sensitive signaling steps leading to GSIS. Based on these findings, we conclude that EHT 1864 specifically inhibits glucose-induced Rac1 activation and membrane association and associated downstream signaling events culminating in inhibition of GSIS.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic β-cells

Sidarala

Veluthakal

Syeda

et al. 2015

Cellular Signalling

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“…Rho proteins are central regulators of multiple intracellular processes, and it is interesting how signaling downstream from Rho has evolved to coordinate cytoskeletal remodeling in conjunction with other processes required for immune cell functions. These include many non-cytoskeletal-related functions such as regulation of gene transcription (69–72), calcium flux (73, 74), and oxidative burst (75–77). …”

Section: Protein Processing In Activated Neutrophilsmentioning

confidence: 99%

Granule Protein Processing and Regulated Secretion in Neutrophils

et al. 2014

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Neutrophils are part of a family of granulocytes that, together with eosinophils and basophils, play an essential role in innate immunity. Neutrophils are the most abundant circulating leukocytes and are vital for rapid immune responses, being recruited to sites of injury or infection within minutes, where they can act as specialized phagocytic cells. However, another prominent function of neutrophils is the release of pro-inflammatory compounds, including cytokines, chemokines, and digestive enzymes, which are stored in intracellular compartments and released through regulated exocytosis. Hence, an important feature that contributes to rapid immune responses is capacity of neutrophils to synthesize and store pre-formed pro-inflammatory mediators in specialized intracellular vesicles and thus no new synthesis is required. This review will focus on advancement in three topics relevant to neutrophil secretion. First, we will examine what is known about basal level pro-inflammatory mediator synthesis, trafficking, and storage in secretory compartments. Second, we will review recent advancements in the mechanisms that control vesicle mobilization and the release of pre-formed mediators. Third, we will examine the upregulation and de novo synthesis of pro-inflammatory mediators by neutrophils engaged at sites of infection.

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“…Vav1 recruitment to the LAT complex in activated mast cells suggests that Rho signaling also has a role in inflammatory processes. Indeed, a role for multiple classes of Rho GTPases in degranulation has been established [9,[13][14][15][16][17]. As central regulators of actin-related morphologies, each member of the Rho GTPase family has a unique role in mediating actin remodeling.…”

Section: Introductionmentioning

confidence: 99%

The effect of Rho drugs on mast cell activation and degranulation

Sheshachalam

Baier

Eitzen

2017

Journal of Leukocyte Biology

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Mast cells are tissue-resident immune cells that produce potent proinflammatory mediators, which are stored in cytoplasmic granules. Stimulation triggers degranulation, a process that mobilizes granules to dock and fuse to the plasma membrane, releasing mediators. Mast cell degranulation has an important role in immunity but can also intensify inflammation and contribute to allergic disorders. Hence, it is important to understand signaling pathways that regulate mast cell degranulation. Here, we examined the role of Rho proteins in regulating mast cell activation leading to degranulation. RBL-2H3 cells and bone marrow-derived mast cells (BMMCs) were stimulated through aggregation of FcεRI receptors. Stimulated cells showed a large increase in the levels of activated Rac and, to a lesser extent, RhoA. Drugs were used to acutely inhibit the function of specific Rho proteins. The Rac inhibitor EHT-1864 and the RhoA inhibitor rhosin inhibited degranulation. Microscopic characterization showed that, upon stimulation, RBL-2H3 cells formed surface ridges that grew into large protrusions reminiscent of circular dorsal ruffles, which flattened into large lamellipodia. LysoTracker-labeled cells showed granules stream into peripheral protrusions. EHT-1864 reduced granule motility, whereas rhosin increased motility; both drugs affected the formation of peripheral protrusions. These results showed that, in response to stimuli, Rho proteins control discrete cytoskeletal remodeling processes that are needed for granule exocytosis. Rac is required to stimulate the remodeling of mast cells, triggering actin-mediated flattening of the cell periphery to create an active degranulation zone, whereas RhoA controls the streaming of highly motile granules into the active zone.

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Rac1 and Rac2 control distinct events during antigen-stimulated mast cell exocytosis

Cited by 20 publications

References 64 publications

EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic β-cells

EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic β-cells

Granule Protein Processing and Regulated Secretion in Neutrophils

The effect of Rho drugs on mast cell activation and degranulation

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