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Department of Cell and Developmental Biology, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
Leukocyte transendothelial migration (TEM) has been modeled as a multistep process beginning with rolling adhesion, followed by firm adhesion, and ending with either transcellular or paracellular passage of the leukocyte across the endothelial monolayer. In the case of paracellular TEM, endothelial cell (EC) junctions are transiently disassembled to allow passage of leukocytes. Numerous lines of evidence demonstrate that tyrosine phosphorylation of adherens junction proteins, such as vascular endothelial cadherin (VE-cadherin) and 
-catenin, correlates with the disassembly of junctions. However, the role of tyrosine phosphorylation in the regulation of junctions during leukocyte TEM is not completely understood. Using human leukocytes and EC, we show that ICAM-1 engagement leads to activation of two tyrosine kinases, Src and Pyk2. Using phospho-specific Abs, we show that engagement of ICAM-1 induces phosphorylation of VE-cadherin on tyrosines 658 and 731, which correspond to the p120-catenin and -catenin binding sites, respectively. These phosphorylation events require the activity of both Src and Pyk2. We find that inhibition of endothelial Src with PP2 or SU6656 blocks neutrophil transmigration (71.1 ± 3.8% and 48.6 ± 3.8% reduction, respectively), whereas inhibition of endothelial Pyk2 also results in decreased neutrophil transmigration (25.5 ± 6.0% reduction). Moreover, overexpression of the nonphosphorylatable Y658F or Y731F mutants of VE-cadherin impairs transmigration of neutrophils compared with overexpression of wild-type VE-cadherin (32.7 ± 7.1% and 38.8 ± 6.5% reduction, respectively). Our results demonstrate that engagement of ICAM-1 by leukocytes results in tyrosine phosphorylation of VE-cadherin, which is required for efficient neutrophil TEM.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants HL 080166 and HL 45100 from the National Institutes of Health and a Kenan Distinguished Professorship (to K.B.). J.D.v.B. is supported by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences.
2 Address correspondence and reprint requests to Dr. Michael J. Allingham, 12-026 Lineberger Comprehensive Cancer Center, CB 7295 School of Medicine, University of North Carolina, Chapel Hill, NC 27599. E-mail address: michael_allingham{at}med.unc.edu
3 Current address: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands.
4 Abbreviations used in this paper: TEM, transendothelial migration; EC, endothelial cell; VE-cadherin, vascular endothelial cadherin.
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