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

Ikeda, Satoshi; Yamaoka‐Tojo, Minako; Hilenski, Lula; Patrushev, Nikolay; Anwar, Ghulam M.; Quinn, Mark T.; Ushio‐Fukai, Masuko

doi:10.1161/01.atv.0000187472.55437.af

Cited by 121 publications

(116 citation statements)

References 37 publications

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“…For example, AQP3 facilitates cell migration through an EGF/EGFr dependent pathway (52) and can mediate wound healing in the epidermis via cell migration and proliferation through p38 MAPK-dependent pathways (43). In addition, several reports have suggested a relationship between ROS fluxes and cell migration, based on imaging studies using nonspecific ROS indicators at the leading edge of migrating endothelial cells (53,54). Finally, an exciting discovery establishing the involvement of H 2 O 2 signaling in wound repair has been reported recently, in which H 2 O 2 generated by the Duox class of Nox proteins acts as a signaling molecule to attract leukocytes to EGF stimulation can activate a membrane-bound NADPH oxidase (Nox), which will then produce extracellular H 2 O 2 , which can then pass into the cell and modulate intracellular redox signaling.…”

Section: Discussionmentioning

confidence: 99%

Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

Miller

Dickinson²,

Chang³

2010

Proc. Natl. Acad. Sci. U.S.A.

622

466

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Hydrogen peroxide (H 2 O 2 ) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H 2 O 2 to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H 2 O 2 into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new chemoselective fluorescent indicator for H 2 O 2 , directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H 2 O 2 specifically through membranes in mammalian cells. Moreover, we show that intracellular H 2 O 2 accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Noxderived H 2 O 2 signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H 2 O 2 can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.growth factor signaling | redox biology | reactive oxygen species | fluorescent sensor | membrane regulation H ydrogen peroxide (H 2 O 2 ) is garnering increased attention as a molecule involved not only in immune response and oxidative stress, but also as a physiological effector in essential cellular processes (1-5). Seminal contributions have elucidated ligand stimulants (6-10) and enzymatic sources (11-13) for cellular H 2 O 2 production as well as putative downstream targets (14-24), but principles of how this reactive oxygen species (ROS) is spatially and temporally regulated to promote redox signaling over oxidative stress pathways remain insufficiently understood. Because many of the signaling functions of H 2 O 2 rely on its generation by nonphagocytic forms of NADPH (Nox) proteins on the extracellular side of cell membranes, understanding how cells funnel H 2 O 2 toward beneficial pathways in these locales is of significant interest. Despite its reactive nature, H 2 O 2 has been long thought to be freely diffusible across biological membranes in a manner akin to the related canonical small-molecule signal nitric oxide (NO) (25). More recent studies implicate the role of AQP water channels, a class of membrane-spanning proteins that facilitate the diffusion of water and other substrates with varying specificity (26-28), in mediating H 2 O 2 passage across the plasma membrane of reconstituted yeast (29) and plant (30) cells. However, given that the experiments described in these reports utilized nonspecific chemical reagents for determination of the redox signal that was passed into the cell, direct evidence that aquaporins influence the cellular uptake of H 2 O 2 in a na...

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Section: Discussionmentioning

confidence: 99%

Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

Miller

Dickinson²,

Chang³

2010

Proc. Natl. Acad. Sci. U.S.A.

622

466

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“…12,24 One of the initial responses to stimulate EC migration is the loosening of stable cell-cell contacts between ECs, and the molecule primarily responsible for cell-cell adhesions of ECs is the VE-cadherin. Recent studies reveal that IQGAP1 regulates E cadherin-mediated cell-cell adhesion both positively and negatively in epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis

Yamaoka‐Tojo

Tojo

Kim

et al. 2006

ATVB

Self Cite

104

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Objective-Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating reactive oxygen species (ROS) production primarily through the VEGF receptor-2 (VEGFR2). One of the initial responses in established vessels to stimulate angiogenesis is loss of vascular endothelial (VE)-cadherin-based cell-cell adhesions; however, little is known about the underlying mechanisms. IQGAP1 is a novel VEGFR2 binding protein, and it interacts directly with actin, cadherin, and ␤-catenin, thereby regulating cell motility and morphogenesis. Methods and Results-Confocal microscopy analysis shows that IQGAP1 colocalizes with VE-cadherin at cell-cell contacts in unstimulated human endothelial cells (ECs). VEGF stimulation reduces staining of IQGAP1 and VE-cadherin at the adherens junction without affecting interaction of these proteins. Knockdown of IQGAP1 using siRNA inhibits localization of VE-cadherin at cell-cell contacts, VEGF-stimulated recruitment of VEGFR2 to the VE-cadherin/␤-catenin complex, ROS-dependent tyrosine phosphorylation of VE-cadherin, which is required for loss of cell-cell contacts and capillary tube formation. IQGAP1 expression is increased in a mouse hindlimb ischemia model of angiogenesis. Conclusions-IQGAP1 is required for establishment of cell-cell contacts in quiescent ECs. To induce angiogenesis, it may function to link VEGFR2 to the VE-cadherin containing adherens junctions, thereby promoting VEGF-stimulated, ROS-dependent tyrosine phosphorylation of VE-cadherin and loss of cell-cell contacts. (Arterioscler Thromb Vasc

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“…It is also interesting to note that IQGAP2 and SOD1 can both associate with GDP-and GTP-bound forms of Rac1 (19,55,120), although in the case of SOD1 there is a nucleotide preference that is dependent on the redox-state of Rac1 (55). IQGAP1 has been shown to increase ROS production by activating Nox2, and in this manner facilitates migratory wound healing in vascular endothelial cells (65). However, it is currently unclear if IQGAP2 also influences Nox activation.…”

Section: Iqgap2mentioning

confidence: 99%

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter

Anklesaria

Choi

et al. 2009

Antioxidants & Redox Signaling

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Enhanced redox-stress caused by neuroinflammation, mitochondria, and NADPH oxidases has been hypothesized to play critical roles in disease progression of amyotrophic lateral sclerosis (ALS). However, distinguishing whether the redox-stress observed in ALS is due to a primary defect in cellular reactive oxygen species metabolism=catabolism, or is a secondary consequence of neuroinflammation, has been difficult and the issue remains a matter of debate. Emerging evidence suggests that defects in genes that regulate NADPH oxidases may account for at least some forms of ALS. NADPH oxidases are key signaling complexes that influence cellular responses to growth factors and cytokines. In this context, NADPH oxidase-derived reactive oxygen species exert spatial control over the redox-dependent activation of certain pro-inflammatory receptors. Understanding the biology of how NADPH oxidases control cell signaling may help to clarify how genetic determinants of ALS lead to dysregulated pro-inflammatory signaling. This review provides a framework for understanding endosomal signaling through NADPH oxidases and potential mechanisms whereby gene defects in various forms of ALS may influence this cellular process and lead to motor neuron degeneration. Lastly, this review discusses past and current efforts to treat ALS using antioxidant therapies, as well as the limitations and advantages of each of these approaches. Antioxid. Redox Signal. 11, 1569-1586.

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

Cited by 121 publications

References 37 publications

Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

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