title: Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer.
abstract: TGF-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.
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. davidwittemail@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. franziskazeeh@gmx.de.
authors.forename: Franziska
authors.initials: F
authors.lastname: Zeeh
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. T.Gaedeken@web.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gädeken
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. frank.gieseler@uksh.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Gieseler
authors.affiliation: Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, D-17487 Greifswald, Germany. bernhard.rauch@uni-greifswald.de.
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Rauch
authors.affiliation: Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany. utz.settmacher@med.uni-jena.de.
authors.forename: Utz
authors.initials: U
authors.lastname: Settmacher
authors.affiliation: Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany. roland.kaufmann@med.uni-jena.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. hendrik.lehnert@uni-luebeck.de.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany. hendrik.ungefroren@uksh.de.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ungefroren
keywords: ALK5; GDF15; PAR2; TGF-β; cachexia; myostatin; pancreatic carcinoma; signaling