XPLN, a Guanine Nucleotide Exchange Factor for RhoA and RhoB, But Not RhoC

Arthur, William T.; Ellerbroek, Shawn M.; Der, Channing J.; Burridge, Keith; Wennerberg, Krister

doi:10.1074/jbc.m207401200

Cited by 125 publications

(151 citation statements)

References 44 publications

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“…Active GEFs preferentially interact with guanine nucleotide-free forms of the small GTPases. A point mutation of glycine to alanine of residue 15 on Rac1 decreases its nucleotide binding (24). After stimulation of Cos-7 cells cotransfected with TrkB and C1199 Tiam1 with BDNF, the level of Tiam1 that was precipitated with Rac1G15A showed a marked increase (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1D), suggesting that Tiam1 is involved in this signaling pathway. Next, to examine whether Tiam1 is activated after stimulation with BDNF, we carried out an affinityprecipitation assay to detect active Tiam1 by using GSTRac1G15A, a guanine nucleotide-free form of Rac1 (24). Active GEFs preferentially interact with guanine nucleotide-free forms of the small GTPases.…”

Section: Resultsmentioning

confidence: 99%

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TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Miyamoto

Yamauchi

Tanoue

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

135

132

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Small GTPases of the Rho family play key roles in the formation of neuronal axons and dendrites by transducing signals from guidance cues, such as neurotrophins, to the actin cytoskeleton. However, there is little insight into the mechanism by which neurotrophins regulate Rho GTPases. Here, we show the crucial role of the ubiquitous Rac1-specific guanine nucleotide exchange factor, Tiam1 (T lymphoma invasion and metastasis 1), in transducing a neurotrophin-mediated change in cell shape. We demonstrate that BDNF, acting through TrkB, directly binds and specifically activates Tiam1 by phosphorylating Tyr-829, leading to Rac1 activation and lamellipodia formation in Cos-7 cells and increased neurite outgrowth from cortical neurons. A point mutation in Tiam1, Tyr-829 to Phe-829, blocked these BDNF-induced changes in cellular morphology. The findings are evidence of a previously uncharacterized mechanism for the activation of Tiam1 and of a role for this effector in neurotrophin-mediated signal transduction leading to changes in cellular morphology.actin ͉ cortical neuron ͉ neurotrophin ͉ Rho guanine nucleotide exchange factors ͉ Rho GTPases

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Miyamoto

Yamauchi

Tanoue

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

135

132

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“…51 for a recent review). It is possible that the pathways leading to cytoskeletal versus gene regulation diverge at the very beginning of the isoprenylation step and that different members of the Rho family initiate different cascades (52)(53)(54)(55)(56)(57)(58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration-and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-␣. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-␣ but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.High levels of cholesterol, and in particular of cholesterol esters (1), influence the generation and aggregation of ␤-amyloid peptides in dissociated cell cultures (2-6) and transgenic mice (7). Patients with high plasma cholesterol levels and cardiovascular diseases have increased risk of Alzheimer's disease (AD) 1 (8 -10), and there is evidence that statins, a family of compounds that inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase: HMG-CoA reductase), decrease the incidence of the disease (11, 12). These observations have led to an extensive and ongoing evaluation of statins as preventive treatments for Alzheimer's disease (13-16).Mevalonate, a cholesterol precursor, the synthesis of which is blocked by statins, is converted into several bioactive compounds. Among these, the isoprenoids are of particular importance because, among other functions, they provide for the covalent addition of lipid moieties (prenylation) to regulatory proteins (17) and thereby affect critical cell functions. Prenylation by the mevalonate products farnesyl diphosphate and geranylgeranyl diphosphate, ...

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“…This technique is based on the concept that GEFs bind small GTPases with high affinity when the GTPase is in a transitional nucleotide-free state [16,26]. As such, the nucleotide-free Rac1 mutant G15ARac1 has higher affinity for binding active GEFs, and our laboratory has used this mutant previously to bind and identify active GEFs [16].…”

Section: Exchange Factor Vav2 Couples Vegf Signaling To Rac1mentioning

confidence: 99%

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

Garrett

Buul

Burridge

2007

Experimental Cell Research

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132

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Vascular endothelial growth factor (VEGF) signaling is critical for both normal and diseaseassociated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the Rho family of small GTPases. As a member of this family, Rac1 promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. To form these membrane protrusions, Rac1 is activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. The goal of this study was to identify the GEF responsible for activating Rac1 in response to VEGF stimulation. We have found that VEGF stimulates biphasic activation of Rac1 and for these studies we focused on the peak of activation that occurs at 30 min. Inhibition of VEGFR-2 signaling blocks VEGF-induced Rac1 activation. Using a Rac1 nucleotide-free mutant (G15ARac1), which has a high affinity for binding activated GEFs, we show that the Rac GEF Vav2 associates with G15ARac1 after VEGF stimulation. Additionally, we show that depleting endothelial cells of endogenous Vav2 with siRNA prevents VEGF-induced Rac1 activation. Moreover, Vav2 is tyrosine phosphorylated upon VEGF treatment, which temporally correlates with Rac1 activation and requires VEGFR-2 signaling and Src kinase activity. Finally, we show that depressing Vav2 expression by siRNA impairs VEGF-induced endothelial cell migration. Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1.

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XPLN, a Guanine Nucleotide Exchange Factor for RhoA and RhoB, But Not RhoC

Cited by 125 publications

References 44 publications

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

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