Modulation of serine protease HTRA1 activity by heparan sulfate proteoglycans

Abstract

The human HTRA1 enzyme (High-Temperature Requirement protein A1, Q92743 Uniprot) is a 51 kDa non-glycosylated serine protease located primarily in the extracellular environment. This enzyme is involved in the remodeling of the extracellular matrix (ECM) by degrading its components, such as decorim, fibronectin, aggrecam and collagen. The mode of action of HTRA1 is related to its serine protease domain of the trypsin family, as well as to its PDZ domain of interaction with other proteins. New findings point to the fact that HTRA1 could interact with Heparan Sulfate Proteoglycans (HSPGs) at the cell surface in a PDZ-dependent manner. It is possible, therefore, that the compartmentalization of HTRA1 at the cell surface by HSPGs may allow the interactions of this protease with the ECM. Thus, the main objective of this project is to study the role of HSPGs in cellular trafficking of the HTRA1 enzyme; in the control of its activity; and in the modulation of cellular signaling controlled by HTRA1 in normal and physiological states, as well as in neoplasia. (AU)