Figure 7

Schematic of the direct and indirect contributions of hepsin to alter ECM integrity. Firstly, hepsin activity is known to modulate cell motility via laminin 332⁵². Hepsin activates the uPA/plasminogen/plasmin cascade and also processes latent hepatocyte growth factor (HGF) leading to HGF/cMet signaling; together, these promote metastasis and altered epithelial cohesion^30,53. Moreover, hepsin can activate pro-matriptase¹⁷ which leads to PAR2 activation and subsequent expression of proMMP-3 and proMMP-1⁵ as well as inflammatory mediators including IL-8⁵⁴ leading to chemotaxis of inflammatory cells such as neutrophils and mast cells. Plasmin⁵⁵, as well as hepsin, generate active MMP-3 which is a prime activator of many proMMPs including proMMP-1 and proMMP-13, key collagen-degrading proteinases. Inflammation induces the expression of prohepsin which auto-activates^17,38 and can directly activate proMMP-1 as well as cleave within the aggrecan IGD to promote both aggrecanolysis and collagenolysis to further impair the structural integrity of tissues.