Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136522.58649.60
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 8, 2004
Revised on June 11, 2004
Accepted on June 11, 2004
IQGAP1, a Novel Vascular Endothelial Growth Factor Receptor Binding Protein, Is Involved in Reactive Oxygen Species-Dependent Endothelial Migration and Proliferation
Minako Yamaoka-Tojo ;
From the Division of Cardiology, Department of Medicine (M.Y.-T., M.U.-F., L.H., S.I.D., T.T., T.F., M.F., N.A.P., R.W.A.), Emory University, Atlanta, Ga; Cardiovascular Research Institute (Y.E.C.), Morehouse School of Medicine, Atlanta, Ga; Division of Cardiology (C.D.K.), Duke University Medical Center, Durham, NC; and the Departments of Biology and Cell Biology (N.W., G.S.B.), University of Virginia, Charlottesville, Va.
* To whom correspondence should be addressed. E-mail: mfukai{at}emory.edu.
Endothelial cell (EC) proliferation and migration are important for reendothelialization and angiogenesis. We have demonstrated that reactive oxygen species (ROS) derived from the small GTPase Rac1-dependent NAD(P)H oxidase are involved in vascular endothelial growth factor (VEGF)-mediated endothelial responses mainly through the VEGF type2 receptor (VEGFR2). Little is known about the underlying molecular mechanisms. IQGAP1 is a scaffolding protein that controls cellular motility and morphogenesis by interacting directly with cytoskeletal, cell adhesion, and small G proteins, including Rac1. In this study, we show that IQGAP1 is robustly expressed in ECs and binds to the VEGFR2. A pulldown assay using purified proteins demonstrates that IQGAP1 directly interacts with active VEGFR2. In cultured ECs, VEGF stimulation rapidly promotes recruitment of Rac1 to IQGAP1, which inducibly binds to VEGFR2 and which, in turn, is associated with tyrosine phosphorylation of IQGAP1. Endogenous IQGAP1 knockdown by siRNA shows that IQGAP1 is involved in VEGF-stimulated ROS production, Akt phosphorylation, endothelial migration, and proliferation. Wound assays reveal that IQGAP1 and phosphorylated VEGFR2 accumulate and colocalize at the leading edge in actively migrating ECs. Moreover, we found that IQGAP1 expression is dramatically increased in the VEGFR2-positive regenerating EC layer in balloon-injured rat carotid artery. These results suggest that IQGAP1 functions as a VEGFR2-associated scaffold protein to organize ROS-dependent VEGF signaling, thereby promoting EC migration and proliferation, which may contribute to repair and maintenance of the functional integrity of established blood vessels.
Key words: IQGAP1 • reactive oxygen species • vascular endothelial growth factor • endothelial cell • cell migration
This article has been cited by other articles:
 |
|
 |
|
  P. V. Usatyuk, I. A. Gorshkova, D. He, Y. Zhao, S. K. Kalari, J. G. N. Garcia, and V. Natarajan Phospholipase D-mediated Activation of IQGAP1 through Rac1 Regulates Hyperoxia-induced p47phox Translocation and Reactive Oxygen Species Generation in Lung Endothelial Cells J. Biol. Chem., May 29, 2009; 284(22): 15339 - 15352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ruiz de Almodovar, D. Lambrechts, M. Mazzone, and P. Carmeliet Role and Therapeutic Potential of VEGF in the Nervous System Physiol Rev, April 1, 2009; 89(2): 607 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hu, B. Shi, M. J. Jarzynka, J.-J. Yiin, C. D'Souza-Schorey, and S.-Y. Cheng ADP-Ribosylation Factor 6 Regulates Glioma Cell Invasion through the IQ-Domain GTPase-Activating Protein 1-Rac1-Mediated Pathway Cancer Res., February 1, 2009; 69(3): 794 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Bogatkevich, A. Ludwicka-Bradley, C. B. Singleton, J. R. Bethard, and R. M. Silver Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L603 - L611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kim, Y.-S. Lee, J. Choe, H. Lee, Y.-M. Kim, and D. Jeoung CD44-Epidermal Growth Factor Receptor Interaction Mediates Hyaluronic Acid-promoted Cell Motility by Activating Protein Kinase C Signaling Involving Akt, Rac1, Phox, Reactive Oxygen Species, Focal Adhesion Kinase, and MMP-2 J. Biol. Chem., August 15, 2008; 283(33): 22513 - 22528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakamura, N. Patrushev, H. Inomata, D. Mehta, N. Urao, H. W. Kim, M. Razvi, V. Kini, K. Mahadev, B. J. Goldstein, et al. Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell-Cell Adhesions in Endothelial Cells Circ. Res., May 23, 2008; 102(10): 1182 - 1191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kowanetz and N. Ferrara Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 173 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shilo, S. Roy, S. Khanna, and C. K. Sen Evidence for the Involvement of miRNA in Redox Regulated Angiogenic Response of Human Microvascular Endothelial Cells Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 471 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jadeski, J. M. Mataraza, H.-W. Jeong, Z. Li, and D. B. Sacks IQGAP1 Stimulates Proliferation and Enhances Tumorigenesis of Human Breast Epithelial Cells J. Biol. Chem., January 11, 2008; 283(2): 1008 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Dise, M. R. Frey, R. H. Whitehead, and D. B. Polk Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration Am J Physiol Gastrointest Liver Physiol, January 1, 2008; 294(1): G276 - G285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Md. R. Abid, K. C. Spokes, S.-C. Shih, and W. C. Aird NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways J. Biol. Chem., November 30, 2007; 282(48): 35373 - 35385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Balenci, Y. Saoudi, D. Grunwald, J. C. Deloulme, A. Bouron, A. Bernards, and J. Baudier IQGAP1 Regulates Adult Neural Progenitors In Vivo and Vascular Endothelial Growth Factor-Triggered Neural Progenitor Migration In Vitro J. Neurosci., April 25, 2007; 27(17): 4716 - 4724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Bensenor, H.-M. Kan, N. Wang, H. Wallrabe, L. A. Davidson, Y. Cai, D. A. Schafer, and G. S. Bloom IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly J. Cell Sci., February 15, 2007; 120(4): 658 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Qin, H. Zeng, and D. Zhao Requirement of Protein Kinase D Tyrosine Phosphorylation for VEGF-A165-induced Angiogenesis through Its Interaction and Regulation of Phospholipase C{gamma} Phosphorylation J. Biol. Chem., October 27, 2006; 281(43): 32550 - 32558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Balenci, I. D. Clarke, P. B. Dirks, N. Assard, F. Ducray, A. Jouvet, M.-F. Belin, J. Honnorat, and J. Baudier IQGAP1 Protein Specifies Amplifying Cancer Cells in Glioblastoma Multiforme. Cancer Res., September 15, 2006; 66(18): 9074 - 9082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamaoka-Tojo, T. Tojo, H. W. Kim, L. Hilenski, N. A. Patrushev, L. Zhang, T. Fukai, and M. Ushio-Fukai IQGAP1 Mediates VE-Cadherin-Based Cell-Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 1991 - 1997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kowanetz and N. Ferrara Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective Clin. Cancer Res., September 1, 2006; 12(17): 5018 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai Redox signaling in angiogenesis: Role of NADPH oxidase Cardiovasc Res, July 15, 2006; 71(2): 226 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moldovan, K. Mythreye, P. J. Goldschmidt-Clermont, and L. L. Satterwhite Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1 Cardiovasc Res, July 15, 2006; 71(2): 236 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ikeda, M. Yamaoka-Tojo, L. Hilenski, N. A. Patrushev, G. M. Anwar, M. T. Quinn, and M. Ushio-Fukai IQGAP1 Regulates Reactive Oxygen Species-Dependent Endothelial Cell Migration Through Interacting With Nox2 Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2295 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Noritake, T. Watanabe, K. Sato, S. Wang, and K. Kaibuchi IQGAP1: a key regulator of adhesion and migration J. Cell Sci., May 15, 2005; 118(10): 2085 - 2092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Golub and P. Caroni PI(4,5)P2-dependent microdomain assemblies capture microtubules to promote and control leading edge motility J. Cell Biol., April 11, 2005; 169(1): 151 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ikeda, M. Ushio-Fukai, L. Zuo, T. Tojo, S. Dikalov, N. A. Patrushev, and R. W. Alexander Novel Role of ARF6 in Vascular Endothelial Growth Factor-Induced Signaling and Angiogenesis Circ. Res., March 4, 2005; 96(4): 467 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Md. R. Abid, I. G. Schoots, K. C. Spokes, S.-Q. Wu, C. Mawhinney, and W. C. Aird Vascular Endothelial Growth Factor-mediated Induction of Manganese Superoxide Dismutase Occurs through Redox-dependent Regulation of Forkhead and I{kappa}B/NF-{kappa}B J. Biol. Chem., October 15, 2004; 279(42): 44030 - 44038. [Abstract] [Full Text] [PDF]
|
|