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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/L1263    most recent 00191.2006v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Beaufort, N. Articles by Pidard, D. Search for Related Content PubMed PubMed Citation Articles by Beaufort, N. Articles by Pidard, D.

The human airway trypsin-like protease modulates the urokinase receptor (uPAR, CD87) structure and functions

¹Inserm, E0336, Paris, France; ²Institute Pasteur, Unité de Défense Innée et Inflammation, Département Infection et Epidémiologie, Paris, France; ³Department of Obstetrics and Gynaecology, Technical University of Munich, Munich, Germany; ⁴Pharmaceutical Discovery Research Laboratories, Teijin Institute of Bio-Medical Research, Teijin Limited, Tokyo, Japan; ⁵Department of Nutrition and Metabolism, Graduate School of Nutrition and Bioscience, The University of Tokushima, Tokushima, Japan; and ⁶Institute of Pathology, Technical University of Munich, Munich, Germany

Submitted 1 June 2006 ; accepted in final form 12 January 2007

The human airway trypsin-like protease (HAT) is a respiratory epithelium-associated, type II transmembrane serine protease, which is also detected as an extracellular enzyme in lung fluids during airway inflammatory disorders. We have evaluated its capacity to affect the urokinase-type plasminogen activator receptor (uPAR), a membrane glycolipid-anchored, three-domain (D1D2D3) glycoprotein that plays a crucial role in innate immunity and inflammation by supporting cell migration and matrix degradation, with structure and biological properties that can be regulated via limited endoproteolysis. With the use of immunoblotting, flow immunocytometry, and ELISA analyses applied to a recombinant uPAR protein and to uPAR-expressing monocytic and human bronchial epithelial cells, it was shown that exposure of uPAR to soluble HAT in the range of 10–500 nM resulted in the proteolytic processing of the full-length (D1D2D3) into the truncated (D2D3) species, with cleavage occurring in the D1 to D2 linker sequence after arginine residues at position 83 and 89. Using immunohistochemistry, we found that both HAT and uPAR were expressed in the human bronchial epithelium. Moreover, transient cotransfection in epithelial cells showed that membrane coexpression of the two partners produced a constitutive and extensive shedding of the D1 domain, occurring for membrane-associated HAT concentrations in the nanomolar range. Because the truncated receptor was found to be unable to bind two of the major uPAR ligands, the adhesive matrix protein vitronectin and the serine protease urokinase, it thus appears that proteolytic regulation of uPAR by HAT is likely to modulate cell adherence and motility, as well as tissue remodeling during the inflammatory response in the airways.

urokinase-type plasminogen activator receptor; human bronchial epithelial cells; human monocytes; lung inflammation

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