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 proteaseactivated 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.

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

“…Moreover, an NF‐κB inhibitor suppressed the HAI‐1 loss‐mediated enhancement of tumorigenicity in Apc Min/+ mice . Protease‐activated receptor‐2 is known to activate NF‐κB signaling in various human cancers, including colon cancer, and HAI‐1 regulates PAR‐2‐activating TTSPs . Thus, the activation of NF‐κB in HAI‐1‐deficient intestine might result from the excessive activation of PAR‐2.…”

“…Nuclear factor‐κB signaling has important roles in cancer progression, primarily through its stimulation of cell proliferation, survival, and angiogenesis . In this regard, activation of PAR‐2 by an extracellular trypsin‐like serine protease transduces NF‐κB signaling . Although several in vitro studies have reported that PAR‐2 promotes the proliferation of human colon cancer cell lines, the role of PAR‐2 in colorectal cancer has not been addressed in vivo.…”

“…Specific cleavage by trypsin‐like serine proteases frees an endogenous ligand for interaction with the core of the receptor, inducing a conformational change that triggers signal transduction . Type II transmembrane serine proteases are known to activate PAR‐2 and PAR‐2 reportedly contributes to tumor progression through its promotion of invasive growth by cancer cells and by stimulating angiogenesis . Among TTSPs, matriptase is the most potent PAR‐2 activator known in epithelial and tumor tissues .…”

“…Type II transmembrane serine proteases are known to activate PAR‐2 and PAR‐2 reportedly contributes to tumor progression through its promotion of invasive growth by cancer cells and by stimulating angiogenesis . Among TTSPs, matriptase is the most potent PAR‐2 activator known in epithelial and tumor tissues . Transgenic expression of matriptase in murine keratinocytes induces skin carcinogenesis that is entirely dependent on PAR‐2 signaling .…”

CRISPR-Cas-amplified urine biomarkers for multiplexed and portable cancer diagnostics

“…We observed the expected preferential cleavage of metalloprotease-responsive nanosensors in CRC-bearing mice and the activation of a serine protease-sensitive substrate (PAP9) that was reported in the lung. This pattern could point to an imbalance of serine protease/protease inhibitors in the pulmonary tumor microenvironment [40][41][42] . Due to the differences in proteolytic networks present in mouse models and human diseases, additional work to be completed before clinical translation may include an evaluation of the sensor performance in the context of additional animal models with comorbidities, and also in human samples.…”