Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2-Mediated Signaling: Co-Conspirators in Cancer Progression

Abstract

Pericellular proteolysis provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Recent advances demonstrate that pericellular proteases can also communicate directly to cells by activation of a unique group of transmembrane G-protein-coupled receptors (GPCR) known as protease-activated receptors (PAR). In this review, we discuss the specific roles of one of four mammalian PARs, namely PAR-2, which is overexpressed in advanced stage tumors and is activated by trypsin-like serine proteases that are highly expressed or otherwise dysregulated in many cancers. We highlight recent insights into the ability of different protease agonists to bias PAR-2 signaling and the newly emerging evidence for an interplay between PAR-2 and membrane-anchored serine proteases, which may co-conspire to promote tumor progression and metastasis. Interfering with these pathways might provide unique opportunities for the development of new mechanism-based strategies for the treatment of advanced and metastatic cancers.

Figure 1.. Activation of PAR-2 by membrane-anchored and secreted serine proteases and implications in cancer.

Human PAR-2 is cleaved by its various agonists on the cell surface at the canonical cleavage site, R³⁶, revealing the S³⁷LIGKV peptide sequence as a tethered ligand (in red text). Membrane-anchored serine proteases are illustrated with their conserved catalytic domains containing the serine (S), aspartate (D) and histidine (H) residues, their respective extracellular domains (low density lipoprotein (LDL) receptor class A domains (indicated by red circles labeled ‘L’), Cls/Clr, urchin embryonic growth factor and bone morphogenic protein 1 (CUB) domains, sea urchin sperm protein, enterokinase, agrin (SEA), and group A scavenger receptor (SR) domains), as well as their respective membrane-tethering regions. Testisin and matriptase cleave PAR-2 directly at the trypsin cleavage site, while prostasin, hepsin, TMPRSS2, and TF:FVIIa/Xa complex have been shown to activate matriptase and thus indirectly activate PAR-2. Upon proteolytic cleavage, PAR-2 can couple to various G proteins or once phosphorylated, bind to β-arrestin; both outcomes can activate subsequent signaling pathways and influencing tumor cell behavior. It is possible that various membrane-anchored serine proteases are capable of activating similar, overlapping, or distinct signaling responses to induce various cellular responses depending on the context.