Non-redundant roles of the Gab1 and Gab2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells

Caron, Christine; Spring, Kathleen; Laramée, Mélanie; Chabot, Catherine; Cloutier, Monikca; Gu, Haihua; Royal, Isabelle

doi:10.1016/j.cellsig.2009.02.004

Cited by 37 publications

(46 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our experiments, mutation of tyrosine 1175 on VEGFR-2 was effective in blocking phosphorylation of PLC␥ but did not have any effect on ARF1 activation suggesting that phosphorylation of tyrosine 801 only, might regulate the ARF1/Akt/eNOS/NO signaling axis. Phosphorylation of both tyrosine 801 and 1214 on VEGFR-2 was shown to be important for the phosphorylation of Gab1, a scaffolding adaptor protein, and activation of Akt, Erk1/2, and Src (53,54). In our experiments, mutation of tyrosine 801 significantly impaired ARF1 and eNOS activation.…”

Section: Discussionsupporting

confidence: 47%

Vascular Endothelial Growth Factor Receptor-2 Activates ADP-ribosylation Factor 1 to Promote Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

Daher

Boulay

Desjardins

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF) induces angiogenesis and regulates endothelial function via production and release of nitric oxide (NO), an important signaling molecule. The molecular basis leading to NO production involves phosphatidylinositiol-3 kinase (PI3K), Akt, and endothelial nitricoxide synthase (eNOS) activation. In this study, we have examined whether small GTP-binding proteins of the ADPribosylation factor (ARF) family act as molecular switches to regulate signaling cascades activated by VEGF in endothelial cells. Our results show that this growth factor can promote the rapid and transient activation of ARF1. In endothelial cells, this GTPase is present on dynamic plasma membrane ruffles. Inhibition of ARF1 expression, using RNA interference, markedly impaired VEGF-dependent eNOS phosphorylation and NO production by preventing the activation of the PI3K/Akt signaling axis. Furthermore, our data indicate that phosphorylation of Tyr 801 , on VEGF receptor 2, is essential for activating Src-and ARF1-dependent signaling events leading to NO release from endothelial cells. Lastly, this mediator is known to regulate a broad variety of endothelial cell functions. Depletion of ARF1 markedly inhibits VEGF-dependent increase of vascular permeability as well as capillary tubule formation, a process important for angiogenesis. Taken together, our data indicate that ARF1 is a novel modulator of VEGF-stimulated NO release and signaling in endothelial cells.

show abstract

Section: Discussionsupporting

confidence: 47%

Vascular Endothelial Growth Factor Receptor-2 Activates ADP-ribosylation Factor 1 to Promote Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

Daher

Boulay

Desjardins

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In cells seeded on Col-IV, VEGF-A induced the formation of podosomes capable of degrading the underlying matrix, whereas, in cells seeded on laminin, VEGF-A induced inactive podosomes proteolytically. VEGF-A activates Src and this can occur through several pathways (Caron et al, 2009;Meyer et al, 2008;Sun et al, 2012). On Col-IV, VEGF-A stimulation increased Src autophosphorylation, p190RhoGAP-B relocalisation and MT1-MMP cell surface exposure at podosome sites whereas these events did not occur on laminin, thus suggesting differences in VEGF-A signalling on these two matrices.…”

Section: Discussionmentioning

confidence: 77%

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

Daubon

Spuul

Alonso

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Podosomes are dynamic cell-matrix contact structures that combine several key abilities, including adhesion, matrix degradation and mechanosensing. These actin-based cytoskeletal structures are well known in monocytic cells, but much less is known about those formed in other lineages. In this study, we characterize podosomes in capillary-derived microvascular endothelial cells. We identify two types of podosomes: constitutive podosomes that form in the absence of specific stimulation and induced podosomes that arise in response to the angiogenic factor VEGF-A. Constitutive and VEGF-A-induced podosomes share similar components but exhibit marked differences in terms of gelatinolytic activity. We also show that extracellular matrix proteins are key determinants of the VEGF-A response: laminin and collagen-IV, but neither collagen-I nor fibronectin are conducive for podosome induction. Moreover, only collagen-IV elicits the formation of proteolytically active podosomes through a mechanism involving increased Src phosphorylation, p190RhoGAP-B relocalisation and MT1-MMP cell surface exposure at podosome sites. We hypothesise that by promoting podosome formation, VEGF-A enables endothelial cells to overcome the basement membrane barrier for sprouting away from the existing vasculature.

show abstract

“…The plasmids encoding hemagglutinin (HA)-tagged murine Gab1 and Gab2 were provided by Morag Park (McGill University, Canada) and Isabelle Royal (University of Montreal, Montreal, Quebec, Canada), respectively, and described previously (20,21). The vectors encoding constitutively active forms of Ras (G12V) and MEK1 (MEK-DD) and the inactive form of Ras (S17N) were described previously (22,23).…”

Section: Methodsmentioning

confidence: 99%

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

Zhang

Lavoie

Fort

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

The scaffolding adapter protein Gab2 (Grb2-associated binder) participates in the signaling response evoked by various growth factors and cytokines. Gab2 is overexpressed in several human malignancies, including breast cancer, and was shown to promote mammary epithelial cell migration. The role of Gab2 in the activation of different signaling pathways is well documented, but less is known regarding the feedback mechanisms responsible for its inactivation. We now demonstrate that activation of the Ras/mitogen-activated protein kinase (MAPK) pathway promotes Gab2 phosphorylation on basic consensus motifs. More specifically, we show that RSK (p90 ribosomal S6 kinase) phosphorylates Gab2 on three conserved residues, both in vivo and in vitro. Mutation of these phosphorylation sites does not alter Gab2 binding to Grb2, but instead, we show that Gab2 phosphorylation inhibits the recruitment of the tyrosine phosphatase Shp2 in response to growth factors. Expression of an unphosphorylatable Gab2 mutant in mammary epithelial cells promotes an invasion-like phenotype and increases cell motility. Taken together, these results suggest that RSK is part of a negative-feedback loop that restricts Gab2-dependent epithelial cell motility. On the basis of the widespread role of Gab2 in receptor signaling, these findings also suggest that RSK plays a regulatory function in diverse receptor systems.

show abstract

Non-redundant roles of the Gab1 and Gab2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells

Cited by 37 publications

References 80 publications

Vascular Endothelial Growth Factor Receptor-2 Activates ADP-ribosylation Factor 1 to Promote Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

Vascular Endothelial Growth Factor Receptor-2 Activates ADP-ribosylation Factor 1 to Promote Endothelial Nitric-oxide Synthase Activation and Nitric Oxide Release from Endothelial Cells

VEGF-A stimulates podosome-mediated collagen-IV proteolysis in microvascular endothelial cells

Gab2 Phosphorylation by RSK Inhibits Shp2 Recruitment and Cell Motility

Contact Info

Product

Resources

About