Vav2 Activates Rac1, Cdc42, and RhoA Downstream from Growth Factor Receptors but Not β1 Integrins

Liu, Betty P.; Burridge, Keith

doi:10.1128/mcb.20.19.7160-7169.2000

Cited by 181 publications

(199 citation statements)

References 54 publications

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“…Rac1 activity is regulated by GEFs and Rho GTPase-activating proteins (GAPs), and Vav2 has been shown to stimulate membrane ruffling and motility when overexpressed (Liu and Burridge, 2000;Marignani and Carpenter, 2001). Additional pathways leading to Rac1 activation also involve paxillin, as paxillin has been shown to participate in the targeting of active Rac1 to the membrane via an interaction with PKL, an ARF-GAP (Turner et al, 1999;Kondo et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Nek3 is structurally related to the cell cycle regulatory kinase NIMA (Never In Mitosis A) of Aspergillus nidulans (Tanaka and Nigg, 1999) and displays a typical serine/ threonine protein kinase domain within its N-terminal half (Tanaka and Nigg, 1999). Vav2 has been shown to activate Rac1, RhoA and Cdc42 (Schuebel et al, 1998;Abe et al, 2000;Liu and Burridge, 2000), and elimination of 183 amino-terminal residues is sufficient to activate its oncogenic potential (Schuebel et al, 1996). PRL-mediated activation of Rac1 in Chinese hamster ovary (CHO) cells has been shown to require not only Vav2 but also Nek3 kinase activity.…”

Section: Introductionmentioning

confidence: 99%

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Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

et al. 2007

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Prolactin (PRL) stimulates the cytoskeletal re-organization and motility of breast cancer cells. During PRL receptor signaling, Vav2 becomes phosphorylated and activated, an event regulated by the serine/threonine kinase Nek3. Given the regulatory role of Vav2, the function of Nek3 in PRL-mediated motility and invasion was examined. Overexpression of Nek3 in Chinese hamster ovary transfectants potentiated cytoskeletal re-organization in response to PRL. In contrast, downregulation of Nek3 expression by small-interfering RNA (siRNA) attenuated PRL-mediated cytoskeletal reorganization, activation of GTPase Rac1, cell migration and invasion of T47D cells. In addition, PRL stimulation induced an interaction between Nek3 and paxillin and significantly increased paxillin serine phosphorylation, whereas Nek3 siRNA-transfected cells showed a marked reduction in paxillin phosphorylation. Analysis of breast tissue microarrays also demonstrated a significant up-regulation of Nek3 expression in malignant versus normal specimens. These data suggest that Nek3 contributes to PRLmediated breast cancer motility through mechanisms involving Rac1 activation and paxillin phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

et al. 2007

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“…Vav2 rabbit antiserum was generated previously and used as previously described [13]. Vav2 rabbit polyclonal antibody (pAb) used for GST-G15ARac1 pulldown was obtained from Zymed (San Francisco, CA).…”

Section: Antibodies and Pharmacological Reagentsmentioning

confidence: 99%

“…It has been shown that several GEFs activate Rac1 in response to EGF and PDGF signaling [13,[23][24][25]. To determine which exchange factors activate Rac1 downstream of VEGF, we first investigated the endogenous expression of candidate Rac1 GEFs in endothelial cells.…”

Section: Exchange Factor Vav2 Couples Vegf Signaling To Rac1mentioning

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%

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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

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130

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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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Structural basis for a novel interaction between TXNIP and Vav2

Zong

et al. 2016

FEBS Letters

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Edited by Lukas Alfons HuberThioredoxin-interacting protein (TXNIP) is a multifunctional protein involved in diverse cellular processes such as cell proliferation and apoptosis. TXNIP stability is controlled by the ubiquitin-proteasome pathway, and the E3 ubiquitin ligase Itch directly interacts with TXNIP via PPxY motifs of TXNIP. In a previously published study, we have shown that phosphorylation of the PPxY tyrosyl residue switches TXNIP selectivity between different binding partners. Here, we describe that tyrosine-phosphorylated PPxY motifs also bind to SH2 domains of Vav2 and Src with dissociation constants around 10 lM and that phosphorylation is indispensable for these interactions as well. The crystal structure of the complex between a phosphorylated PPxY motif, and the SH2 domain of Vav2 reveals a conserved recognition mechanism.

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Vav2 Activates Rac1, Cdc42, and RhoA Downstream from Growth Factor Receptors but Not β1 Integrins

Cited by 181 publications

References 54 publications

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

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

Structural basis for a novel interaction between TXNIP and Vav2

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