Matriptase

Matriptase, or ST14, is a type II transmembrane serine protease of the serine protease family. It is expressed mainly on the surface of epithelial cells in tissues such as skin, the gastrointestinal tract, and glandular ducts. As a membrane-anchored protease, matriptase participates in proteolytic cascades essential for epithelial development, differentiation, and barrier function.

It is synthesized as an inactive zymogen anchored to the cell surface by a short cytoplasmic tail and a single transmembrane domain, with the serine protease active site facing the extracellular milieu. Activation occurs by proteolytic removal of an activation segment, and its activity is tightly regulated by extracellular inhibitors, notably HAI-1 and HAI-2 (encoded by SPINT1 and SPINT2).

Matriptase can activate and modulate multiple substrates and pathways on the epithelial surface. Notably, it can activate the serine protease prostasin (PRSS8) in an epithelial protease cascade that promotes barrier maturation. It also participates in processing and activating other proteases and can influence signaling through protease-activated receptor-2 (PAR-2) and growth factor pathways in certain contexts, including hepatocyte growth factor activation in some settings. Its activity contributes to epidermal differentiation, wound healing, and maintenance of the skin barrier.

Genetic disruption of ST14 in humans causes autosomal recessive ichthyosis with hypotrichosis or related congenital ichthyoses, reflecting a critical role in skin barrier formation. In mice, loss of matriptase leads to severe developmental defects and perinatal lethality related to epithelial barrier failure. In cancer, matriptase is frequently overexpressed in carcinomas and is linked to tumor invasion and metastasis, in part by promoting activation of proteolytic cascades and growth factor signaling. Regulation by inhibitors SPINT1 and SPINT2 is an important control point in these processes.