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Transforming growth factor- β (TGF- β ), serine proteinases such as trypsin, and proteinase-activated receptor 2 (PAR2) promote tumor development by stimulating invasion and metastasis. Previously, we found that in cancer cells derived from pancreatic ductal adenocarcinoma (PDAC) PAR2 protein is necessary for TGF- β 1-dependent cell motility. Here, we show in the same cells that, conversely, the type I TGF- β receptor activin receptor-like kinase 5 is dispensable for trypsin and PAR2 activating peptide (PAR2-AP)-induced migration. To reveal whether G q -calcium signaling is a prerequisite for PAR2 to enhance TGF- β signaling, we investigated the effects of PAR2-APs, PAR2 mutation and PAR2 inhibitors on TGF- β 1-induced migration, reporter gene activity, and Smad activation. Stimulation of cells with PAR2-AP alone failed to enhance basal or TGF- β 1-induced C-terminal phosphorylation of Smad3, Smad-dependent activity of a luciferase reporter gene, and cell migration. Consistently, in complementary loss of function studies, abrogation of the PAR2-G q -calcium signaling arm failed to suppress TGF- β 1-induced cell migration, reporter gene activity, and Smad3 activation. Together, our findings suggest that the calcium-regulating motif is not required for PAR2 to synergize with TGF- β 1 to promote cell motility. Additional experiments in PDAC cells revealed that PAR2 and TGF- β 1 synergy may involve TGF- β 1 induction of enzymes that cause autocrine cleavage/activation of PAR2, possibly through a biased signaling function. Our results suggest that although reducing PAR2 protein expression may potentially block TGF- β 's prooncogenic function, inhibiting PAR2-G q -calcium signaling alone would not be sufficient to achieve this effect.

molecular pharmacology

Transforming Growth Factor-<i>β</i>1/Activin Receptor-like Kinase 5-Mediated Cell Migration is Dependent on the Protein Proteinase-Activated Receptor 2 but not on Proteinase-Activated Receptor 2-Stimulated G<sub>q</sub>-Calcium Signaling

Transforming Growth Factor-β1/Activin Receptor-like Kinase 5-Mediated Cell Migration is Dependent on the Protein Proteinase-Activated Receptor 2 but not on Proteinase-Activated Receptor 2-Stimulated Gq-Calcium Signaling

Transforming Growth Factor-β1/Activin Receptor-like Kinase 5-Mediated Cell Migration is Dependent on the Protein Proteinase-Activated Receptor 2 but not on Proteinase-Activated Receptor 2-Stimulated G_q-Calcium Signaling