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J. Clin. Med. 2016, 5(12), 111; doi:10.3390/jcm5120111

Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer

1
First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of Lübeck, D-23538 Lübeck, Germany
2
Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, D-17487 Greifswald, Germany
3
Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Andrei Turtoi
Received: 3 November 2016 / Revised: 22 November 2016 / Accepted: 28 November 2016 / Published: 30 November 2016
(This article belongs to the Special Issue Biological and Clinical Aspects of TGF-beta in Carcinogenesis)
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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. View Full-Text
Keywords: pancreatic carcinoma; signaling; TGF-β; ALK5; PAR2; myostatin; GDF15; cachexia pancreatic carcinoma; signaling; TGF-β; ALK5; PAR2; myostatin; GDF15; cachexia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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.

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