Mechanism of Epidermal Growth Factor Regulation of Vav2, a Guanine Nucleotide Exchange Factor for Rac

Tamás, Péter; Solti, Zita; Bauer, Petra; Illés, András; Sipeki, Szabolcs; Bauer, Andras J.; Farago, Anna F.; Downward, Julian; Buday, László

doi:10.1074/jbc.m207555200

Cited by 104 publications

(85 citation statements)

References 39 publications

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“…Vav2 is regulated by tyrosine phosphorylation and/or membrane targeting, but the exact regulatory mechanism is controversial. Vav2 is tyrosine phosphorylated in response to EGF and PDGF signaling and this phosphorylation correlates with enhanced migration of fibroblasts [13,27,46]. However, it is still unclear whether this tyrosine phosphorylation directly regulates Vav2 exchange activity.…”

Section: Discussionmentioning

confidence: 99%

“…Given that Vav2 is tyrosine phosphorylated in response to EGF and PDGF signaling, and that tyrosine phosphorylation has been associated with Vav2 activation [13,27], we examined the tyrosine phosphorylation of Vav2 following VEGF treatment. We found that Vav2 tyrosine phosphorylation was stimulated by VEGF and peaked at 30 min of VEGF stimulation (Fig.…”

Section: Vav2 Is Tyrosine Phosphorylated In Response To Vegfmentioning

confidence: 99%

“…4B). It has been shown previously that phosphorylation of tyrosine 172 in Vav2 relieves an intramolecular inhibition, potentially resulting in increased activity of Vav2 by allowing access to the DH domain [27,35]. Using a phosphospecific antibody, we explored whether Vav2 was specifically phosphorylated at tyrosine 172 upon VEGF treatment.…”

Section: Tyrosine Phosphorylation Of Vav2 Is Mediated By Srcmentioning

confidence: 99%

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

Garrett

Buul

Burridge

2007

Experimental Cell Research

152

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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Section: Discussionmentioning

confidence: 99%

Section: Vav2 Is Tyrosine Phosphorylated In Response To Vegfmentioning

confidence: 99%

Section: Tyrosine Phosphorylation Of Vav2 Is Mediated By Srcmentioning

confidence: 99%

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

Garrett

Buul

Burridge

2007

Experimental Cell Research

152

132

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“…Anti-Tyr-172 Vav2 antibodies were used since EGFR phosphorylates Vav2 at its N-terminal domain, specifically, Tyr-142, Tyr-159, and Tyr-172 (51).…”

Section: Methodsmentioning

confidence: 99%

“…Activation of Rac1 can be mediated by multiple mechanisms, including activation of tyrosine kinase receptors, such as the EGFR (38,51). It has been shown that loss of integrin ␣1␤1 leads to upregulated EGFR tyrosine phosphorylation (39).…”

Section: Fig 7 Ros Partially Contribute To Increased Egfr Phosphorymentioning

confidence: 99%

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Chen¹,

Abair²,

Ibanez³

et al. 2007

Molecular and Cellular Biology

100

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Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin ␣1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by ␣1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin ␣1-null mesangial cells produce excessive ROS. Integrin ␣1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in ␣1-null mesangial cells. Thus, our study demonstrates that integrin ␣1␤1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.Integrin ␣1␤1, a major collagen binding receptor, is expressed in different cell types, including fibroblasts (45), endothelial cells (8), and mesangial cells in the glomerulus of the kidney (30, 53). Integrin ␣1␤1 confers the ability of cells to bind to collagenous substrata, including collagens I and IV (4, 45), and to proliferate on these substrata (45). Moreover, cells expressing integrin ␣1␤1 sense extracellular levels of collagen and downregulate its synthesis at both transcriptional and translational levels (4,14). Finally, we demonstrated that integrin ␣1␤1 also downregulates the production of reactive oxygen species (ROS) (4, 58).Following renal injury, mice lacking integrin ␣1␤1 develop more extensive glomerular fibrosis characterized by excessive accumulation of collagen type IV compared to wild-type (WT) mice (4, 58). Increased fibrosis is due to both a direct effect of the lack of integrin ␣1␤1-mediated downregulation of collagen IV synthesis and excessive ROS production by ␣1-null mesangial cells.Constitutive production of ROS by mesangial cells, a major cell type found in the glomerulus of the kidney, originates from an intrinsic NADPH oxidase (26, 48) that normally functions at a low level and increases in response to inflammatory stimuli, high glucose, or stress (25,34,35,37,55). The NADPH oxidase, highly characterized in phagocytes, is a multicomponent enzyme complex that consists of the membrane-bound cytochrome b 558 (p22 phox and gp91 phox ) and cytoplasmic proteins (p40 phox , p47 phox , p67 phox ) that translocate to the membrane following cellular stimulation to produce superoxide (3, 9, 47). A multicomponent phagocyte-like NADPH oxidase is also a major source of ROS in many nonphagocytic cells, including mesangial cells. In the phagocyte-like NADPH oxidase, the catalytic subunits are termed Nox proteins, with ...

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Vav2 is required for Netrin‐1 receptor‐class‐specific spinal motor axon guidance

Tsou

Wang

Chang

et al. 2021

Developmental Dynamics

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Background: Proper guidance of neuronal axons to their targets is required to assemble neural circuits during the development of the nervous system. However, the mechanism by which the guidance of axonal growth cones is regulated by specific intermediaries activated by receptor signaling pathways to mediate cytoskeleton dynamics is unclear. Vav protein members have been proposed to mediate this process, prompting us to investigate their role in the limb selection of the axon trajectory of spinal lateral motor column (LMC) neurons.Results: We found Vav2 and Vav3 expression in LMC neurons when motor axons grew into the limb. Vav2, but not Vav3, loss-of-function perturbed LMC pathfinding, while Vav2 gain-of-function exhibited the opposite effects, demonstrating that Vav2 plays an important role in motor axon growth. Vav2 knockdown also attenuated the redirectional phenotype of LMC axons induced by Dcc, but not EphA4, in vivo and lateral LMC neurite growth preference to Netrin-1 in vitro. This study showed that Vav2 knockdown and ectopic nonphosphorylable Vav2 mutant expression abolished the Src-induced stronger growth preference of lateral LMC neurites to Netrin-1, suggesting that Vav2 is downstream of Src in this context.Yi-Syue Tsou and Chih-Yang Wang contributed equally to this study.

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Mechanism of Epidermal Growth Factor Regulation of Vav2, a Guanine Nucleotide Exchange Factor for Rac

Abstract: Vav2 is a member of the

Cited by 104 publications

References 39 publications

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

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

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Vav2 is required for Netrin‐1 receptor‐class‐specific spinal motor axon guidance

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