Membrane-anchored serine proteases as regulators of epithelial function

Abstract

Cleavage of proteins in the extracellular milieu, including hormones, growth factors and their receptors, ion channels, and various cell adhesion and extracellular matrix molecules, plays a key role in the regulation of cell behavior. Among more than 500 proteolytic enzymes encoded by mammalian genomes, membrane-anchored serine proteases (MASPs), which are expressed on the surface of epithelial cells of all major organs, are excellently suited to mediate signal transduction across the epithelia and are increasingly being recognized as important regulators of epithelial development, function, and disease [ 1–3]. In this minireview, we summarize current knowledge of the in vivo roles of MASPs in acquisition and maintenance of some of the defining functions of epithelial tissues, such as barrier formation, ion transport, and sensory perception.

Proteases and HPV-Induced Carcinogenesis

“…As part of this family, there is a subgroup composed of membrane-anchored serine proteases, which is divided into (i) GPI-serine proteases that are anchored in the plasma membrane by a glycosylphosphatidylinositol anchor, (ii) Type I-serine proteases that have a single pass domain in the plasma membrane located close to the C-terminus end, and (iii) Type II-serine proteases that are anchored in the plasma membrane and have an anchor sign located close to the N-terminus end [77,82].…”

“…Different studies have shown that when matriptase is less expressed, there is also less activation of uPA in the cells of ovary and prostate cancer [87,88]. Matriptase is also responsible for activating the PI3K-Akt-mTOR pathway after the proteolytic activation of the hepatocyte growth factor precursor (pro-HGF), which can promote cell proliferation and decrease apoptosis [82]. PAR-2 (protease-activated receptor 2), a receptor expressed in different cell types, is related to cell adhesion, the maintenance of the skin barrier, and inflammatory responses [89,90].…”

Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel’s γ-subunit

“…Importantly, in expression systems ENaC can be fully activated by coexpressing membraneanchored serine proteases (43)(44)(45)(46). The family of membrane-anchored serine proteases consists of 20 members identified in human to date (47)(48)(49). They share a conserved extracellular catalytic domain and J o u r n a l P r e -p r o o f 4 are anchored directly to the plasma membrane via a GPI-anchor or a transmembrane domain.…”

Hepsin: a multifunctional transmembrane serine protease in pathobiology

“…Depending on the similarity in modular arrangements in the stem region, TTSPs can be divided into four subgroups, that is, hepsin (also known as TMPRSS1), matriptase, HAT, and corin subgroups [12,13]. Members of the TTSP family are expressed in many tissues, where they participate in diverse processes, including food digestion [14], epithelial differentiation [15,16], intestinal barrier function [17][18][19], skin permeability [20][21][22], sodium homeostasis [23,24], iron metabolism [25], and vascular remodeling [26,27]. TTSP deficiencies or overexpression has been reported in patients with malnutrition [14], skin defects [28,29], intestinal disease [30], iron deficiency anemia [25], hypertension [31,32], kidney disease [33], and cancer [34].…”