2017
DOI: 10.3390/ijms18122776
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The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility

Abstract: Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA interference was used to deplete cells of PAR2, … Show more

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Cited by 23 publications
(18 citation statements)
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“…The collagenase derived PAR2 peptide LIGKVD-NH 2 induces biased Mitogen-activated protein kinase (MAPK) phosphorylation -MAPK phosphorylation is a well characterised downstream output of canonical PAR2 activation (25)(26)(27). Indeed, herein we confirm that SLIGKV-NH 2 (Fig.…”
Section: Resultssupporting
confidence: 72%
“…The collagenase derived PAR2 peptide LIGKVD-NH 2 induces biased Mitogen-activated protein kinase (MAPK) phosphorylation -MAPK phosphorylation is a well characterised downstream output of canonical PAR2 activation (25)(26)(27). Indeed, herein we confirm that SLIGKV-NH 2 (Fig.…”
Section: Resultssupporting
confidence: 72%
“…Protumorigenic activities attributed to PAR-2 signaling include chemokinesis, cell proliferation, invasion and migration, inflammatory signaling, and increased angiogenesis ( Fig. 1) in several tumor types including breast, oral, renal, pancreatic, gastric, lung, and esophageal cancers (36)(37)(38)(39)…”
Section: Par-2 Signaling and Cancermentioning
confidence: 99%
“…It is likely that membrane-anchored serine proteases in proximity to PAR-2 will be a critical consideration in the development of such therapies. Many attempts to develop PAR-2-biased agonists (148) and antagonists (15,37) have been modeled on analogues of the PAR-2-activating peptide, some of which are capable of preferentially modulating Ca 2þ or ERK1/2 signaling (148). Other small molecules and antibodies are being developed to target binding pockets and transmembrane regions, as well as allosteric sites on PAR-2, in an effort to prevent conformational changes required for receptor activation upon proteolytic cleavage or to prevent tethered ligand binding to the peptide-binding site (149)(150)(151).…”
Section: Implications and Future Directionsmentioning
confidence: 99%
“…However, a potential functional interaction between TGF-β and PAR signaling in controlling these processes has not been anticipated until our own analysis. We previously demonstrated the essential role of ERK for TGF-β- and PAR2-mediated cell motility in pancreatic tumor cells [ 92 ]. Along the same lines, analysis of signal transduction pathways activated upon PAR2 stimulation in HaCaT keratinocytes showed an involvement of ERK1/2 and profound EGFR transactivation, leading to secretion of TGF-β1 [ 68 ].…”
Section: Cancermentioning
confidence: 99%