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(American Journal of Pathology. 2005;166:1247-1258.)
© 2005 American Society for Investigative Pathology

Receptor Protein Tyrosine Phosphatase µ Regulates the Paracellular Pathway in Human Lung Microvascular Endothelia

Xiu Fen Sui*, Timothy D. Kiser*, Sang Won Hyun*, Daniel J. Angelini*, Robert L. Del Vecchio{dagger}, Bradford A. Young*, Jeffrey D. Hasday*, Lewis H. Romer{ddagger}, Antonino Passaniti*, Nicholas K. Tonks{dagger} and Simeon E. Goldblum*

From the Departments of Medicine and Pathology,* Division of Infectious Diseases and Pulmonary Medicine, Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland; Cold Spring Harbor Laboratory,{dagger} Cold Spring, New York; and the Departments of Medicine, Anesthesiology, Cell Biology, and Pediatrics,{ddagger} The Johns Hopkins University School of Medicine, Baltimore, Maryland

The pulmonary vascular endothelial paracellular pathway and zonula adherens (ZA) integrity are regulated, in part, through protein tyrosine phosphorylation. ZA-associated protein tyrosine phosphatase (PTP)s are thought to counterregulate tyrosine phosphorylation events within the ZA multiprotein complex. One such receptor PTP, PTPµ, is highly expressed in lung tissue and is almost exclusively restricted to the endothelium. We therefore studied whether PTPµ, in pulmonary vascular endothelia, associates with and/or regulates both the tyrosine phosphorylation state of vascular endothelial (VE)-cadherin and the paracellular pathway. PTPµ was expressed in postconfluent human pulmonary artery and lung microvascular endothelial cells (ECs) where it was almost exclusively restricted to EC-EC boundaries. In human lung microvascular ECs, knockdown of PTPµ through RNA interference dramatically impaired barrier function. In immortalized human microvascular ECs, overexpression of wild-type PTPµ enhanced barrier function. PTPµ-VE-cadherin interactions were demonstrated through reciprocal co-immunoprecipitation assays and co-localization with double-label fluorescence microscopy. When glutathione S-transferase-PTPµ was incubated with purified recombinant VE-cadherin, and when glutathione S-transferase-VE-cadherin was incubated with purified recombinant PTPµ, PTPµ directly bound to VE-cadherin. Overexpression of wild-type PTPµ decreased tyrosine phosphorylation of VE-cadherin. Therefore, PTPµ is expressed in human pulmonary vascular endothelia where it directly binds to VE-cadherin and regulates both the tyrosine phosphorylation state of VE-cadherin and barrier integrity.




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