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Abstract
Over the last two decades, cell surface proteases belonging to the type II transmembrane serine protease (TTSP) family have emerged as important enzymes in the mammalian degradome, playing critical roles in epithelial biology, regulation of metabolic homeostasis, and cancer. Human airway trypsin-like protease 5 (HATL5) is one of the few family members that remains uncharacterized. Here we demonstrate that HATL5 is a catalytically active serine protease that is inhibited by the two Kunitz type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 and 2, as well as by serpinA1. Full-length HATL5 is localized on the cell surface of cultured mammalian cells as demonstrated by confocal microscopy. HATL5 displays a relatively restricted tissue expression profile, with both transcript and protein present in the cervix, esophagus, and oral cavity. Immunohistochemical analysis revealed an expression pattern where HATL5 is localized on the cell surface of differentiated epithelial cells in the stratified squamous epithelia of all three of these tissues. Interestingly, HATL5 is significantly decreased in cervical, esophageal, and head and neck carcinomas as compared to normal tissue. Analysis of cervical and esophageal cancer tissue arrays demonstrated that the squamous epithelial cells lose their expression of HATL5 protein upon malignant transformation.
Highlights
The type II transmembrane serine proteases are divided into four phylogenetically distinct subfamilies: the human airway trypsin-like (HAT)/differentially expressed in squamous cell carcinoma gene (DESC) subfamily, hepsin/transmembrane protease serine subfamily, matriptase subfamily, and the corin subfamily
These findings suggest that the TMPRSS11b gene likely encodes a functional serine protease
In all three cell lines, a protein product of approximately 60 kDa was detected (Fig. 2B). This apparent molecular mass is significantly higher than the predicted molecular mass of 46 kDa, suggesting that Human airway trypsin-like protease 5 (HATL5) is subject to posttranslational modifications
Summary
The type II transmembrane serine proteases are divided into four phylogenetically distinct subfamilies: the human airway trypsin-like (HAT)/differentially expressed in squamous cell carcinoma gene (DESC) subfamily, hepsin/transmembrane protease serine (hepsin/TMPRSS) subfamily, matriptase subfamily, and the corin subfamily. There is an extensive body of literature documenting critical roles of members of the hepsin/TMPRSS, matriptase, and corin subfamilies in physiological and pathological processes. Critical roles for these TTSPs have been described in diverse areas and include epithelial development and homeostasis, iron metabolism, hearing, digestion, blood pressure regulation, as well as viral infection, inflammation, and oncogenesis [3] [5][6]. A study employing genetic ablation of TMPRSS11A and HAT in mice demonstrated that the two proteases are dispensable for development, general health, and long-term survival in the absence of external challenges or additional genetic deficits [15]
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