Vascular Endothelial Growth Factor Causes Translocation of p47  to Membrane Ruffles through WAVE1

Wu, Ru Feng; Gu, Ying; Xu, You; Nwariaku, Fiemu E.; Terada, Lance S.

doi:10.1074/jbc.m302251200

Cited by 81 publications

(79 citation statements)

References 41 publications

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“…These data contrast with those of Wu et al (78) who showed that VEGF-mediated phosphorylation of JNK was oxidasedependent. Moreover, previous studies in HUVEC have demonstrated a role for ROS in VEGF-mediated activation of ERK1/2 in HUVEC and porcine aortic endothelial cells (23,36).…”

Section: Discussioncontrasting

confidence: 56%

NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

Abid¹,

Spokes²,

Shih

et al. 2007

Journal of Biological Chemistry

137

125

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Vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) play critical roles in vascular physiology and pathophysiology. We have demonstrated previously that NADPH oxidase-derived ROS are required for VEGF-mediated migration and proliferation of endothelial cells. The goal of this study was to determine the extent to which VEGF signaling is coupled to NADPH oxidase activity. Human umbilical vein endothelial cells and/or human coronary artery endothelial cells were transfected with short interfering RNA against the p47 phox subunit of NADPH oxidase, treated in the absence or presence of VEGF, and assayed for signaling, gene expression, and function. We show that NADPH oxidase activity is required for VEGF activation of phosphoinositide 3-kinase-Akt-forkhead, and p38 MAPK, but not ERK1/2 or JNK. The permissive role of NADPH oxidase on phosphoinositide 3-kinase-Akt-forkhead signaling is mediated at post-VEGF receptor levels and involves the nonreceptor tyrosine kinase Src. DNA microarrays revealed the existence of two distinct classes of VEGF-responsive genes, one that is ROS-dependent and another that is independent of ROS levels. VEGF-induced, thrombomodulin-dependent activation of protein C was dependent on NADPH oxidase activity, whereas VEGF-induced decay-accelerating factor-mediated protection of endothelial cells against complement-mediated lysis was not. Taken together, these findings suggest that NADPH oxidase-derived ROS selectively modulate some but not all the effects of VEGF on endothelial cell phenotypes.

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Section: Discussioncontrasting

confidence: 56%

NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

Abid¹,

Spokes²,

Shih

et al. 2007

Journal of Biological Chemistry

137

125

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“…Molecular linkage between actin cytoskeleton and NAD(P)H oxidase has been demonstrated. [23][24][25][26] In ECs, Wu et al 27 reported that VEGF promotes p47 phox translocation to membrane ruffles via direct interaction with WAVE1, a promoter of the actin nucleation complex, which in turn activates NAD(P)H oxidase. Qian et al 28 showed that arsenicinduced NAD(P)H oxidase activation and EC migration are suppressed by cytochalasin D and jasplakinolide.…”

Section: Discussionmentioning

confidence: 99%

IQGAP1 Regulates Reactive Oxygen Species–Dependent Endothelial Cell Migration Through Interacting With Nox2

Ikeda

Yamaoka‐Tojo

Hilenski

et al. 2005

ATVB

121

104

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Objective-Endothelial cell (EC) migration is a key event for repair process after vascular injury and angiogenesis. EC migration is regulated by reorganization of the actin cytoskeleton at the leading edge and localized production of reactive oxygen species (ROS) at the site of injury. However, underlying mechanisms are unclear. We reported that IQGAP1, an actin binding scaffold protein, mediates VEGF-induced activation of gp91phox (Nox2)-dependent NAD(P)H oxidase and EC migration. We thus hypothesized that Nox2 and IQGAP1 may play important roles in ROS-dependent EC migration in response to injury. Methods and Results-Using a monolayer scratch assay with confluent ECs, we show that ROS production is increased at the margin of scratch area and Nox2 translocates to the leading edge, where it colocalizes and associates with both actin and IQGAP1 in migrating ECs. Knockdown of IQGAP1 using siRNA and inhibition of the actin cytoskeleton blocked scratch injury-induced H 2 O 2 production, Nox2 translocation and its interaction with actin, and EC migration toward the injured site. Conclusions-These suggest that IQGAP1 may function to link Nox2 to actin at the leading edge, thereby facilitating ROS production at the site of injury, which may contribute to EC migration. (Arterioscler Thromb Vasc Biol. 2005;25:2295-2300.)Key Words: actin cytoskeleton Ⅲ endothelial cell migration Ⅲ IQGAP1 Ⅲ NAD(P)H oxidase Ⅲ reactive oxygen species E ndothelial migration is a key event during the repair of damaged vessels after vascular injury and angiogenesis, and this may contribute to limiting the development of atherogenesis. 1,2 Cell migration is regulated by the dynamic reorganization of the actin cytoskeleton, protrusion at the front of the cell, and retraction at the rear. It is a highly localized event, involving the generation of spatially and temporally restricted signaling molecules, including the small GTPase Rac1 3 and phosphatidylinositol 3,4,5 trisphosphate [PI(3,4,5)P 3 ], 4 the product of PI 3-kinase, at the site of the new leading edge. Although excess amounts of reactive oxygen species (ROS) are toxic, physiological levels of ROS serve as signaling molecules to regulate many growth and migratory responses. 5,6 ROS are also necessary for reparative angiogenesis in the ischemic heart 7 and hindlimb 8 as well as wound-healing in vivo. 9 The PI 3kinase-Rac pathway is also involved in ROS production. 10 In endothelial cells (ECs), endogenous H 2 O 2 accumulates in actively migrating cells at the site of injury, which is required for cytoskeletal reorganization and cell migration. 11 However, underlying regulatory mechanisms are unclear.In ECs, NAD(P)H oxidase is a major source of ROS. 12 ECs express NAD(P)H oxidase subunits that are identical to those found in phagocytes, including the membrane-bound gp91 phox (now known as Nox2) and p22 phox , the cytosolic components p47 phox and p67 phox , and Rac1. 12 On stimulation, cytosolic components translocate to the membrane to form a multimeric protein complex, leading to product...

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“…Several signalling pathways have been implicated in the formation of dorsal Journal of Cell Science 123 (8) ruffles downstream from RTKs, including PI3K (Dharmawardhane et al, 2000;Scaife and Langdon, 2000) and Rac (Palamidessi et al, 2008) Dowrick et al, 1993;Krueger et al, 2003;Orth et al, 2006;Wu et al, 2003). Gab1 is recruited to each of these RTKs, where it participates in the activation of downstream signalling pathways, including PI3K and Rac (Dance et al, 2006;Gu and Neel, 2003;Jackson et al, 2004;Laramee et al, 2007;Maroun et al, 1999a;Rakhit et al, 2000;Rodrigues et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Dorsal ruffles form in response to stimulation by growth factors such as HGF, EGF, PDGF-bb and vascular endothelial growth factor (VEGF) (Buccione et al, 2004;Dowrick et al, 1993;Wu et al, 2003) and require regulators of actin polymerisation (Buccione et al, 2004) and Rac activity (Krueger et al, 2003;Lanzetti et al, 2004;Palamidessi et al, 2008;Ridley et al, 1992;Suetsugu et al, 2003;Wu et al, 2003). Formation of dorsal ruffles requires localisation of activated Rac to the plasma membrane; for instance, the small GTPase Rab5 is required for HGF-induced dorsal ruffles, as it trafficks activated Rac to the plasma membrane (Lanzetti et al, 2004;Palamidessi et al, 2008), indicating that regulators of Rac localisation to the membrane are crucial for dorsal ruffle formation.…”

Section: Introductionmentioning

confidence: 99%

The Gab1 scaffold regulates RTK-dependent dorsal ruffle formation through the adaptor Nck

Abella

Vaillancourt

Frigault

et al. 2010

Journal of Cell Science

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SummaryThe polarised distribution of signals downstream from receptor tyrosine kinases (RTKs) regulates fundamental cellular processes that control cell migration, growth and morphogenesis. It is poorly understood how RTKs are involved in the localised signalling and actin remodelling required for these processes. Here, we show that the Gab1 scaffold is essential for the formation of a class of polarised actin microdomain, namely dorsal ruffles, downstream from the Met, EGF and PDGF RTKs. Gab1 associates constitutively with the actin-nucleating factor N-WASP. Following RTK activation, Gab1 recruits Nck, an activator of N-WASP, into a signalling complex localised to dorsal ruffles. Formation of dorsal ruffles requires interaction between Gab1 and Nck, and also requires functional N-WASP. Epithelial cells expressing Gab1DNck (Y407F) exhibit decreased Met-dependent Rac activation, fail to induce dorsal ruffles, and have impaired cell migration and epithelial remodelling. These data show that a Gab1-Nck signalling complex interacts with several RTKs to promote polarised actin remodelling and downstream biological responses.

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Vascular Endothelial Growth Factor Causes Translocation of p47 to Membrane Ruffles through WAVE1

Cited by 81 publications

References 41 publications

NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways

IQGAP1 Regulates Reactive Oxygen Species–Dependent Endothelial Cell Migration Through Interacting With Nox2

The Gab1 scaffold regulates RTK-dependent dorsal ruffle formation through the adaptor Nck

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