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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4337-4344. Prepublished online as a Blood First Edition Paper on February 8, 2005; DOI 10.1182/blood-2005-01-0010. This Article Full Text (PDF) All Versions of this Article: 2005-01-0010v1 105/11/4337    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by May, C. Articles by Bohlen, P. Search for Related Content PubMed PubMed Citation Articles by May, C. Articles by Bohlen, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 5, 2005 Accepted January 25, 2005 Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature Chad May, Jacqueline F Doody, Rashed Abdullah, Paul Balderes, Xiaohong Xu, Chien P Chen, Zhenping Zhu, Lawrence Shapiro, Paul Kussie, Daniel J Hicklin, Fang Liao, and Peter Bohlen* ImClone Systems Incorporated, New York, NY, USA Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY, USA * Corresponding author; email: peter.bohlen{at}imclone.com. VE-cadherin is an adhesion molecule localized at the adherens junctions of endothelial cells. It is crucial for the proper assembly of vascular structures during angiogenesis and maintaining vascular integrity. We have studied three monoclonal antibodies (mAbs) against murine VE-cadherin that inhibit angiogenesis and tumor growth. Two of these, BV13 and 10G4, also disrupted normal vessels resulting in severe vascular leakage, while the third, E4G10, did not. The goal of the current report was to identify the epitope of E4G10, and distinguish it from those of the disruptive mAbs. We mapped the epitope of E4G10 to within the first 10 amino acids of mature VE-cadherin, and demonstrate that conserved tryptophan residues in this sequence are required for VE-cadherin mediated trans-adhesion. The disruptive mAbs target a different epitope within amino acids 45-56, which structural homology modeling suggests is not involved in trans-adhesion. From our studies, we hypothesize that E4G10 can only bind the neovasculature, where VE-cadherin has not yet engaged in trans-adhesion and its epitope is fully exposed. Thus, E4G10 can inhibit junction formation and angiogenesis but is unable to target normal vasculature because its epitope is masked. In contrast, BV13 and 10G4 bind an epitope that is accessible regardless of VE-cadherin interactions, leading to the disruption of adherens junctions. Our findings establish the immediate N-terminal region of VE-cadherin as a novel target for inhibiting angiogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Targeting VE-cadherin (while naked, and not engaged) Francesco Bertolini Blood 2005 105: 4157. [Full Text] [PDF] This article has been cited by other articles: G. Berx and F. van Roy Involvement of Members of the Cadherin Superfamily in Cancer Cold Spring Harb Perspect Biol, December 1, 2009; 1(6): a003129 - a003129. [Abstract] [Full Text] [PDF] E. Monaghan-Benson and K. Burridge The Regulation of Vascular Endothelial Growth Factor-induced Microvascular Permeability Requires Rac and Reactive Oxygen Species J. Biol. Chem., September 18, 2009; 284(38): 25602 - 25611. [Abstract] [Full Text] [PDF] L. Shapiro and W. I. Weis Structure and Biochemistry of Cadherins and Catenins Cold Spring Harb Perspect Biol, September 1, 2009; 1(3): a003053 - a003053. [Abstract] [Full Text] [PDF] A. B. Salter, S. K. Meadows, G. G. Muramoto, H. Himburg, P. Doan, P. Daher, L. Russell, B. Chen, N. J. Chao, and J. P. Chute Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo Blood, February 26, 2009; 113(9): 2104 - 2107. [Abstract] [Full Text] [PDF] D. J. Nolan, A. Ciarrocchi, A. S. Mellick, J. S. Jaggi, K. Bambino, S. Gupta, E. Heikamp, M. R. McDevitt, D. A. Scheinberg, R. Benezra, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization Genes & Dev., June 15, 2007; 21(12): 1546 - 1558. [Abstract] [Full Text] [PDF] K. Xiao, J. Garner, K. M. Buckley, P. A. Vincent, C. M. Chiasson, E. Dejana, V. Faundez, and A. P. Kowalczyk p120-Catenin Regulates Clathrin-dependent Endocytosis of VE-Cadherin Mol. Biol. Cell, November 1, 2005; 16(11): 5141 - 5151. [Abstract] [Full Text] [PDF] O. J. Harrison, E. M. Corps, and P. J. Kilshaw Cadherin adhesion depends on a salt bridge at the N-terminus J. Cell Sci., September 15, 2005; 118(18): 4123 - 4130. [Abstract] [Full Text] [PDF]

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