Rac Regulates Vascular Endothelial Growth Factor Stimulated Motility

Soga, Norihito; Connolly, John; Chellaiah, Meenakshi A.; Kawamura, J; Hruska, Keith A.

doi:10.3109/15419060109080703

Cited by 73 publications

(63 citation statements)

References 55 publications

(56 reference statements)

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“…Though several studies showed that VEGF causes endothelial cell migration by inducing Rac1-stimulated lamellipodia formation, the pathway between VEGF signaling and Rac1 activation was not explored [4]. In this study, we identified the exchange factor Vav2 as mediating VEGF signaling to Rac1.…”

Section: Discussionmentioning

confidence: 89%

“…Previous work has shown that VEGF stimulates HUVEC migration [4,5,36]. Since our findings suggested that Vav2 specifically activates Rac1 during VEGF signaling, we investigated whether Vav2 was required for the migration of HUVECs and HMVEC-d towards VEGF.…”

Section: Vav2 Is Necessary For Vegf-induced Endothelial Cell Migrationmentioning

confidence: 92%

“…Previous work has shown that VEGF signaling induces lamellipodia formation and increases the migration of endothelial cells [4][5][6]. During this process, VEGF elicits its biological effects such as migration through VEGF receptor-2 (VEGFR-2), a member of the VEGF family of receptor tyrosine kinases found in endothelial cells [7].…”

Section: Introductionmentioning

confidence: 99%

“…Of these GTPases, active Rac1 has been shown to stimulate cell migration by inducing lamellipodia formation. The effects of VEGF on endothelial cell motility are inhibited when Rac1 activity is perturbed [4], suggesting that VEGF mediates actin remodeling through Rac1.…”

Section: Introductionmentioning

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: 89%

Section: Vav2 Is Necessary For Vegf-induced Endothelial Cell Migrationmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The dysregulated Rac1 activity has been implicated in several aspects of malignant phenotypes such as tumorigenic transformation and outgrowth (21)(22)(23)(24)(25). Rac1 is also integral in the regulation of tumor angiogenesis through its control over epithelial cell motility (26)(27)(28) and endothelial cell permeability (29,30). We (6)(7)(8) and others (31)(32)(33)(34) have shown that Rac1 activity contributes to the resistance of cancer cells to apoptosis by different chemotherapies.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Yoshida

Zhang

Rosado

et al. 2010

Molecular Cancer Therapeutics

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Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line-dependent manner: induction of G 1 cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G 1 cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-κB, but not c-Jun NH 2 -terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-κB-dependent gene products. Mol Cancer Ther; 9(6); 1657-68. ©2010 AACR.

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Growing and shaping the vascular tree: multiple roles for VEGF

Ruhrberg¹

2003

BioEssays

139

120

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Vascular Endothelial Growth Factor (VEGF) is the most potent and ubiquitous vascular growth factor known to date. Yet, prior to its description as a secreted mitogen for endothelial cells, it was identified as a vascular permeability factor. These seemingly disparate avenues of discovery highlight VEGF's ability to control many distinct aspects of endothelial cell behaviour, including proliferation, migration, specialisation and survival. The versatility of VEGF as a patterning molecule is likely linked to its association with various signalling receptor complexes, but also its expression in several isoforms with a differential affinity for heparan sulfate proteoglycans in the extracellular matrix. In contrast to the absolute requirement for all known VEGF receptors, the presence of only a single VEGF isoform is sufficient for vascular development. However, the isoforms serve as exquisite tools for the fine patterning of growing vessel networks during embryogenesis and in postnatal life.

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Rac Regulates Vascular Endothelial Growth Factor Stimulated Motility

Cited by 73 publications

References 55 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

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Growing and shaping the vascular tree: multiple roles for VEGF

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