Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer
AbstractTGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia. View Full-Text
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Witte, D.; Zeeh, F.; Gädeken, T.; Gieseler, F.; Rauch, B.H.; Settmacher, U.; Kaufmann, R.; Lehnert, H.; Ungefroren, H. Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer. J. Clin. Med. 2016, 5, 111.
Witte D, Zeeh F, Gädeken T, Gieseler F, Rauch BH, Settmacher U, Kaufmann R, Lehnert H, Ungefroren H. Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer. Journal of Clinical Medicine. 2016; 5(12):111.Chicago/Turabian Style
Witte, David; Zeeh, Franziska; Gädeken, Thomas; Gieseler, Frank; Rauch, Bernhard H.; Settmacher, Utz; Kaufmann, Roland; Lehnert, Hendrik; Ungefroren, Hendrik. 2016. "Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer." J. Clin. Med. 5, no. 12: 111.