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*
Amgen Institute, Toronto, Ontario, Canada;
Department of Inflammation, Amgen Boulder, Boulder, CO 80301;
Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada;
§
Amgen, Thousand Oaks, CA 91320; and
¶
Department of Pathology, Cornell University Medical College, New York, NY 10021
Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31), a member of the Ig superfamily, is expressed strongly at endothelial cell-cell junctions, on platelets, and on most leukocytes. CD31 has been postulated to play a role in vasculogenesis and angiogenesis, and has been implicated as a key mediator of the transendothelial migration of leukocytes. To further define the physiologic role of CD31, we used targeted gene disruption of the CD31 gene in embryonic stem cells to generate CD31-deficient mice. CD31-deficient mice (CD31KO) are viable and born at the expected Mendelian frequency, remain healthy, and exhibit no obvious vascular developmental defects. In response to inflammatory challenge, polymorphonuclear leukocytes of CD31KO mice are arrested between the vascular endothelium and the basement membrane of inflammatory site mesenteric microvessels, confirming a role for CD31 in the migration of neutrophils through the subendothelial extracellular matrix. Normal numbers of leukocytes are recovered from inflammatory sites in CD31KO mice, however, suggesting that the defect in leukocyte migration across basal lamina observed in the absence of CD31 may be compensated for by the use of other adhesion molecules, or possibly an increased rate of migration. Homing of T lymphocytes in vivo is normal, and CD31KO mice are able to mount a cutaneous hypersensitivity response normally. In addition, CD31-mediated homophilic adhesion does not appear to play a role in platelet aggregation in vitro. This study provides genetic evidence that CD31 is involved in transbasement membrane migration, but does not play an obligatory role in either vascular development or leukocyte migration.
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A. R. Schenkel, T. W. Chew, and W. A. Muller Platelet Endothelial Cell Adhesion Molecule Deficiency or Blockade Significantly Reduces Leukocyte Emigration in a Majority of Mouse Strains J. Immunol., November 15, 2004; 173(10): 6403 - 6408. [Abstract] [Full Text] [PDF]
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G. Bazzoni and E. Dejana Endothelial Cell-to-Cell Junctions: Molecular Organization and Role in Vascular Homeostasis Physiol Rev, July 1, 2004; 84(3): 869 - 901. [Abstract] [Full Text] [PDF]
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R. E. Young, R. D. Thompson, K. Y. Larbi, M. La, C. E. Roberts, S. D. Shapiro, M. Perretti, and S. Nourshargh Neutrophil Elastase (NE)-Deficient Mice Demonstrate a Nonredundant Role for NE in Neutrophil Migration, Generation of Proinflammatory Mediators, and Phagocytosis in Response to Zymosan Particles In Vivo J. Immunol., April 1, 2004; 172(7): 4493 - 4502. [Abstract] [Full Text] [PDF]
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G. W. Payne, J. A. Madri, W. C. Sessa, and S. S. Segal Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H493 - H498. [Abstract] [Full Text] [PDF]
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P. J. Newman and D. K. Newman Signal Transduction Pathways Mediated by PECAM-1: New Roles for an Old Molecule in Platelet and Vascular Cell Biology Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 953 - 964. [Abstract] [Full Text] [PDF]
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A. R. Burns, C. W. Smith, and D. C. Walker Unique Structural Features That Influence Neutrophil Emigration Into the Lung Physiol Rev, April 1, 2003; 83(2): 309 - 336. [Abstract] [Full Text] [PDF]
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C. D. O'Brien, P. Lim, J. Sun, and S. M. Albelda PECAM-1-dependent neutrophil transmigration is independent of monolayer PECAM-1 signaling or localization Blood, April 1, 2003; 101(7): 2816 - 2825. [Abstract] [Full Text] [PDF]
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J. Dangerfield, K. Y. Larbi, M.-T. Huang, A. Dewar, and S. Nourshargh PECAM-1 (CD31) Homophilic Interaction Up-Regulates {alpha}6{beta}1 on Transmigrated Neutrophils In Vivo and Plays a Functional Role in the Ability of {alpha}6 Integrins to Mediate Leukocyte Migration through the Perivascular Basement Membrane J. Exp. Med., November 4, 2002; 196(9): 1201 - 1212. [Abstract] [Full Text] [PDF]
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P. F. Lalor, S. Edwards, G. McNab, M. Salmi, S. Jalkanen, and D. H. Adams Vascular Adhesion Protein-1 Mediates Adhesion and Transmigration of Lymphocytes on Human Hepatic Endothelial Cells J. Immunol., July 15, 2002; 169(2): 983 - 992. [Abstract] [Full Text] [PDF]
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R. Wilkinson, A. B. Lyons, D. Roberts, M.-X. Wong, P. A. Bartley, and D. E. Jackson Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)-mediated activation, and autoimmune disease Blood, June 17, 2002; 100(1): 184 - 193. [Abstract] [Full Text] [PDF]
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M.-X. Wong, D. Roberts, P. A. Bartley, and D. E. Jackson Absence of Platelet Endothelial Cell Adhesion Molecule-1 (CD31) Leads to Increased Severity of Local and Systemic IgE-Mediated Anaphylaxis and Modulation of Mast Cell Activation J. Immunol., June 15, 2002; 168(12): 6455 - 6462. [Abstract] [Full Text] [PDF]
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D. Broide Fast Flowing Eosinophils . Signals for Stopping and Stepping Out of Blood Vessels Am. J. Respir. Cell Mol. Biol., June 1, 2002; 26(6): 637 - 640. [Full Text] [PDF]
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M. Cicmil, J. M. Thomas, M. Leduc, C. Bon, and J. M. Gibbins Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets Blood, January 1, 2002; 99(1): 137 - 144. [Abstract] [Full Text] [PDF]
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S. K. Shaw, B. N. Perkins, Y.-C. Lim, Y. Liu, A. Nusrat, F. J. Schnell, C. A. Parkos, and F. W. Luscinskas Reduced Expression of Junctional Adhesion Molecule and Platelet/Endothelial Cell Adhesion Molecule-1 (CD31) at Human Vascular Endothelial Junctions by Cytokines Tumor Necrosis Factor-{alpha} Plus Interferon-{gamma} Does Not Reduce Leukocyte Transmigration Under Flow Am. J. Pathol., December 1, 2001; 159(6): 2281 - 2291. [Abstract] [Full Text] [PDF]
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K. L. Jones, S. C. Hughan, S. M. Dopheide, R. W. Farndale, S. P. Jackson, and D. E. Jackson Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions Blood, September 1, 2001; 98(5): 1456 - 1463. [Abstract] [Full Text] [PDF]
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M. Miller, K.-L. P. Sung, W. A. Muller, J. Y. Cho, M. Roman, D. Castaneda, J. Nayar, T. Condon, J. Kim, P. Sriramarao, et al. Eosinophil Tissue Recruitment to Sites of Allergic Inflammation in the Lung Is Platelet Endothelial Cell Adhesion Molecule Independent J. Immunol., August 15, 2001; 167(4): 2292 - 2297. [Abstract] [Full Text] [PDF]
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T. M. Carlos Leukocyte recruitment at sites of tumor: dissonant orchestration J. Leukoc. Biol., August 1, 2001; 70(2): 171 - 184. [Abstract] [Full Text] [PDF]
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B. Wang, C. Feliciani, I. Freed, Q. Cai, and D. N. Sauder Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies J. Leukoc. Biol., August 1, 2001; 70(2): 185 - 191. [Abstract] [Full Text] [PDF]
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S. Patil, D. K. Newman, and P. J. Newman Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen Blood, March 15, 2001; 97(6): 1727 - 1732. [Abstract] [Full Text] [PDF]
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R. D. Thompson, K. E. Noble, K. Y. Larbi, A. Dewar, G. S. Duncan, T. W. Mak, and S. Nourshargh Platelet-endothelial cell adhesion molecule-1 (PECAM-1)-deficient mice demonstrate a transient and cytokine-specific role for PECAM-1 in leukocyte migration through the perivascular basement membrane Blood, March 15, 2001; 97(6): 1854 - 1860. [Abstract] [Full Text] [PDF]
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E. Prager, G. Staffler, O. Majdic, M. D. Saemann, S. Godar, G. J. Zlabinger, and H. Stockinger Induction of Hyporesponsiveness and Impaired T Lymphocyte Activation by the CD31 Receptor:Ligand Pathway in T Cells J. Immunol., February 15, 2001; 166(4): 2364 - 2371. [Abstract] [Full Text] [PDF]
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N. ILAN, A. MOHSENIN, L. CHEUNG, and J. A. MADRI PECAM-1 shedding during apoptosis generates a membrane-anchored truncated molecule with unique signaling characteristics FASEB J, February 1, 2001; 15(2): 362 - 372. [Abstract] [Full Text] [PDF]
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S. TOHKA, M.-L. LAUKKANEN, S. JALKANEN, and M. SALMI Vascular adhesion protein 1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo FASEB J, February 1, 2001; 15(2): 373 - 382. [Abstract] [Full Text] [PDF]
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E. Sans, E. Delachanal, and A. Duperray Analysis of the Roles of ICAM-1 in Neutrophil Transmigration Using a Reconstituted Mammalian Cell Expression Model: Implication of ICAM-1 Cytoplasmic Domain and Rho-Dependent Signaling Pathway J. Immunol., January 1, 2001; 166(1): 544 - 551. [Abstract] [Full Text] [PDF]
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 A. Marszalek, T. Daa, K. Kashima, I. Nakayama, and S. Yokoyama Ultrastructural and Morphometric Studies Related to Expression of the Cell Adhesion Molecule PECAM-1/CD31 in Developing Rat Lung J. Histochem. Cytochem., September 1, 2000; 48(9): 1283 - 1290. [Abstract] [Full Text]
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 C. W.Y. Wong, G. Wiedle, C. Ballestrem, B. Wehrle-Haller, S. Etteldorf, M. Bruckner, B. Engelhardt, R. H. Gisler, and B. A. Imhof PECAM-1/CD31 Trans-homophilic Binding at the Intercellular Junctions Is Independent of Its Cytoplasmic Domain; Evidence for Heterophilic Interaction with Integrin alpha vbeta 3 in Cis Mol. Biol. Cell, September 1, 2000; 11(9): 3109 - 3121. [Abstract] [Full Text]
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R. D. Thompson, M. W. Wakelin, K. Y. Larbi, A. Dewar, G. Asimakopoulos, M. A. Horton, M. T. Nakada, and S. Nourshargh Divergent Effects of Platelet-Endothelial Cell Adhesion Molecule-1 and {beta}3 Integrin Blockade on Leukocyte Transmigration In Vivo J. Immunol., July 1, 2000; 165(1): 426 - 434. [Abstract] [Full Text] [PDF]
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K. A. Reedquist, E. Ross, E. A. Koop, R. M.F. Wolthuis, F. J.T. Zwartkruis, Y. van Kooyk, M. Salmon, C. D. Buckley, and J. L. Bos The Small Gtpase, Rap1, Mediates Cd31-Induced Integrin Adhesion J. Cell Biol., March 20, 2000; 148(6): 1151 - 1158. [Abstract] [Full Text] [PDF]
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C. J. Drake and P. A. Fleming Vasculogenesis in the day 6.5 to 9.5 mouse embryo Blood, March 1, 2000; 95(5): 1671 - 1679. [Abstract] [Full Text] [PDF]
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J. R. Allport, W. A. Muller, and F. W. Luscinskas Monocytes Induce Reversible Focal Changes in Vascular Endothelial Cadherin Complex during Transendothelial Migration under Flow J. Cell Biol., January 10, 2000; 148(1): 203 - 216. [Abstract] [Full Text] [PDF]
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C Johnson-Leger, M Aurrand-Lions, and B. Imhof The parting of the endothelium: miracle, or simply a junctional affair? J. Cell Sci., January 3, 2000; 113(6): 921 - 933. [Abstract] [PDF]
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F. Liao, A. R. Schenkel, and W. A. Muller Transgenic Mice Expressing Different Levels of Soluble Platelet/Endothelial Cell Adhesion Molecule-IgG Display Distinct Inflammatory Phenotypes J. Immunol., November 15, 1999; 163(10): 5640 - 5648. [Abstract] [Full Text] [PDF]
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D. K. Newton-Nash and P. J. Newman A New Role for Platelet-Endothelial Cell Adhesion Molecule-1 (CD31): Inhibition of TCR-Mediated Signal Transduction J. Immunol., July 15, 1999; 163(2): 682 - 688. [Abstract] [Full Text] [PDF]
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N. Ilan, L. Cheung, E. Pinter, and J. A. Madri Platelet-Endothelial Cell Adhesion Molecule-1 (CD31), a Scaffolding Molecule for Selected Catenin Family Members Whose Binding Is Mediated by Different Tyrosine and Serine/Threonine Phosphorylation J. Biol. Chem., July 7, 2000; 275(28): 21435 - 21443. [Abstract] [Full Text] [PDF]
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M. Cicmil, J. M. Thomas, T. Sage, F. A. Barry, M. Leduc, C. Bon, and J. M. Gibbins Collagen, Convulxin, and Thrombin Stimulate Aggregation-independent Tyrosine Phosphorylation of CD31 in Platelets. EVIDENCE FOR THE INVOLVEMENT OF Src FAMILY KINASES J. Biol. Chem., August 25, 2000; 275(35): 27339 - 27347. [Abstract] [Full Text] [PDF]
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K.-i. Hirata, T. Ishida, K. Penta, M. Rezaee, E. Yang, J. Wohlgemuth, and T. Quertermous Cloning of an Immunoglobulin Family Adhesion Molecule Selectively Expressed by Endothelial Cells J. Biol. Chem., May 4, 2001; 276(19): 16223 - 16231. [Abstract] [Full Text] [PDF]
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