title: Co-localization of the channel activating protease prostasin/(CAP1/PRSS8) with its candidate activator, matriptase.
abstract: Prostasin (CAP1/PRSS8) is a glycosylphosphatidylinositol-anchored membrane serine protease believed to be critical for the regulation of epithelial sodium channel (ENaC) activity. Prostasin is synthesized as an inactive zymogen that requires a site-specific endoproteolytic cleavage to be converted to an active protease. We have recently reported that the tumor-associated type II transmembrane serine protease, matriptase is necessary and sufficient for prostasin activation in the epidermis. In this study, the interrelationship between the two membrane serine proteases was investigated further by using enzymatic gene trapping combined with immunohistochemistry to delineate the spatial expression of matriptase and prostasin in mouse tissues. We utilized a knock-in mouse with a promoterless beta-galactosidase marker gene inserted into the matriptase locus, as a unique tool for precise assessment of endogenous matriptase expression. The spatial expression of matriptase and prostasin in mouse tissues was delineated by combining in situ beta-galactosidase matriptase staining with immunohistochemical detection of prostasin. We report that prostasin displays a near-ubiquitous co-localization with its candidate activator matriptase in a variety of normal epithelial tissues. These include simple, stratified, and pseudo-stratified epithelium of the integumentary system, digestive tract, respiratory tract, and urogenital tract. However, matriptase and prostasin expression segregates during epithelial multi-stage carcinogenesis to eventually become localized in separate compartments of the tumor. These data suggest that a matriptase-prostasin zymogen activation cascade may be functionally operative in multiple epithelial tissues, but matriptase promotes epithelial carcinogenesis independent of prostasin.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: List
authors.forename: John P
authors.initials: JP
authors.lastname: Hobson
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D000099271:Prostasin
chemical_list: D053503:Epithelial Sodium Channels; D012697:Serine Endopeptidases; D000099271:Prostasin; C485595:matriptase