Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

Abstract

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones.

Soluble Dipeptidyl Peptidase-4 Induces Fibroblast Activation Through Proteinase-Activated Receptor-2

“…To activate SMAD signaling in NIH/3T3 fibroblasts, the requisite concentration of soluble DPP4 is approximately 80-200 ng/ml, whereas the requisite concentration of TGF-b is less than 10 ng/ml. PAR2 plays crucial roles in tissue hemostasis, thrombosis, wound healing, inflammation-associated disorders, fibrosis, and cancer (Ungefroren et al, 2018). PAR2 activation involves receptor cleavage by different serine proteases and exposure to an N-terminal tethered ligand (TL) that binds to and activates the cleaved receptor (Hollenberg et al, 1997).…”

“…PAR2 plays crucial roles in tissue hemostasis, thrombosis, wound healing, inflammation-associated disorders, fibrosis, and cancer ( Ungefroren et al., 2018 ). PAR2 activation involves receptor cleavage by different serine proteases and exposure to an N-terminal tethered ligand (TL) that binds to and activates the cleaved receptor ( Hollenberg et al., 1997 ).…”

CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer

“…This finding is in agreement with the stromal-disrupting effects of nabpaclitaxel documented by Alvarez et al [34], who demonstrated that thanks to nabpaclitaxel the patients treated with the combination GEM/NAB displayed a softer stroma than patients treated with gemcitabine alone, because it became less abundant in CAFs and the collagen fibers were disrupted and disorganized, thus determining tumor softening. This evidence prompted us to investigate signal transduction pathways crucial in the crosstalk between tumor cells and stroma, such as TGF-β and PAR-2 signalling, notoriously involved in pro-fibrotic/pro-inflammatory process in pancreatic cancer [35], as inducers of resistance to GEM/NAB.…”

Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats

“…These receptors mediate the production of proinflammatory cytokines, such as IL-6 and IL-8 [30]. Furthermore, cross-talk occurs between PAR1/2 signaling and TGF-β signaling, which links to tissue fibrosis [31,32]. PAR1/2 deficiency has been reported to be protective against experimental renal ischemia-reperfusion injury [33], crescentic GN [34], diabetic nephropathy [35,36], and unilateral ureteral obstruction [37,38].…”