Matriptase in Skin: Function and Regulation

Abstract

Epidermal differentiation is a carefully orchestrated process that leads to the formation of the critical protective barrier provided by the skin. The process of generating a functional epidermal layer requires progressive remodeling of cell morphology and tissue structure, and involves significant pericellular proteolysis that must be regulated in a precisely controlled manner. In particular, the matriptase-driven protease network plays a critical role in epidermal barrier construction as well as in the regenerative processes required for wound healing. In this dissertation, I have identified and characterized novel molecular mechanisms governing the regulation of matriptase, and cellular mechanisms by which matriptase activates its molecular targets and contributes to keratinocyte differentiation and formation of epidermal barrier. First, I identified plasminogen as a keratinocyte-selective extracellular stimulus for matriptase activation. The discovery of plasminogen as an initiating signal of the protease cascade reaffirms the theory that the matriptase-uPA-plasmin cascade is not unidirectional in the activation of its components, but it is reciprocal. In addition to HAI-1, I also revealed keratinocytes employ antithrombin as a significant endogenous protease inhibitor. The enhanced role of antithrombin in matriptase inhibition in keratinocytes reveals the regulatory adaptation in stratified epithelial cells due to the changes in tissue structure, compared to the polarized epithelial cells. With the dual inhibitory mechanisms, I further revealed that matriptase acts on its molecular targets in two different ways: a rapid activation of prostasin by cell-associated active matriptase under extremely tight control of HAI-1, and the action on several other substrates, including uPA, HGF, and syndecan-1, by secreted active matriptase that is controlled by antithrombin. Last but not least, I also demonstrated that the physiological role of matriptase in human skin likely lies in the basal and spinous keratinocytes that are involved in proliferation and early differentiation. The role of matriptase in the early stages of keratinocyte life history was further supported by the increased matriptase zymogen activation in the keratinocytes of the bulge area. By charactering the prominent regulators, downstream effectors, and the expression and activation states of matriptase in human skin, a clearer picture is emerging regarding the role of matriptase in skin biology.