This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/10/1182    most recent CIRCRESAHA.107.167080v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakamura, Y. Articles by Ushio-Fukai, M. Search for Related Content PubMed PubMed Citation Articles by Nakamura, Y. Articles by Ushio-Fukai, M. Related Collections Angiogenesis

(Circulation Research. 2008;102:1182.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Yoshimasa Nakamura, Nikolay Patrushev, Hyoe Inomata, Dolly Mehta, Norifumi Urao, Ha Won Kim, Masooma Razvi, Vidisha Kini, Kalyankar Mahadev, Barry J. Goldstein, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai

From the Departments of Pharmacology (Y.N., H.I., D.M., N.U., H.W.K., M.R., V.K., R.M., T.F., M.U.-F.) and Medicine (H.W.K., T.F.), University of Illinois at Chicago; Emory University School of Medicine (N.P.), Atlanta, Ga; Division of Endocrinology, Diabetes, and Metabolic Diseases (K.M., B.J.G.), Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa; and Department of Biofunctional Chemistry (Y.N.), Graduate School of Natural Science and Technology, Okayama University, Japan.

Correspondence to Masuko Ushio-Fukai, PhD, Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois at Chicago, 835 S Wolcott, M/C868, E403 MSB, Chicago, IL 60612. E-mail mfukai{at}uic.edu

Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR)2 in tyrosine, which is followed by disruption of VE-cadherin–mediated cell–cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin–mediated cell–cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell–cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo.

Key Words: protein tyrosine phosphatase 1B • vascular endothelial growth factor • endothelial cell • cell–cell adhesions • angiogenesis

This article has been cited by other articles:

				K. Schroder, A. Kohnen, A. Aicher, E. A. Liehn, T. Buchse, S. Stein, C. Weber, S. Dimmeler, and R. P. Brandes NADPH Oxidase Nox2 Is Required for Hypoxia-Induced Mobilization of Endothelial Progenitor Cells Circ. Res., September 11, 2009; 105(6): 537 - 544. [Abstract] [Full Text] [PDF]

				E. J. Belin de Chantemele, K. Muta, J. Mintz, M. L. Tremblay, M. B. Marrero, D. J. Fulton, and D. W. Stepp Protein Tyrosine Phosphatase 1B, a Major Regulator of Leptin-Mediated Control of Cardiovascular Function Circulation, September 1, 2009; 120(9): 753 - 763. [Abstract] [Full Text] [PDF]