Fig. 3.

Proposed mechanism by which HPSE activates ERK signaling. HPSE may induce syndecan-1 shedding in an enzymatically dependent manner and HGF upregulation in an enzymatically independent manner. Downstream Met signaling results in p-ERK formation. Another mechanism involves the HPSE-mediated VEGF activation which can lead to p-ERK activation. p-ERK can stimulate uPA, uPAR, and pro-MMP9 expression which leads to syndecan-1 shedding. Shed syndecan-1 forms a complex with VEGF as described before, and the downstream VEGF signaling can activate ERK. Finally, enzymatically active HPSE can activate PKC, which up-regulates IRS-1, and the IR, which phosphorylates IRS-1. p-IRS-1 can then stimulate ERK activation