{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:28:41Z","timestamp":1787614121443,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2016,11,30]],"date-time":"2016-11-30T00:00:00Z","timestamp":1480464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>TGF-\u03b2 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-\u03b2 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-\u03b21-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-\u03b2-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-\u03b2 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-\u03b2 type I receptor ALK5, PAR2 may also impact signaling by other TGF-\u03b2 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.<\/jats:p>","DOI":"10.3390\/jcm5120111","type":"journal-article","created":{"date-parts":[[2016,11,30]],"date-time":"2016-11-30T10:10:36Z","timestamp":1480500636000},"page":"111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-\u03b2 Signaling in Pancreatic Cancer"],"prefix":"10.3390","volume":"5","author":[{"given":"David","family":"Witte","sequence":"first","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Zeeh","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"G\u00e4deken","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6409-3822","authenticated-orcid":false,"given":"Frank","family":"Gieseler","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6003-4662","authenticated-orcid":false,"given":"Bernhard","family":"Rauch","sequence":"additional","affiliation":[{"name":"Department of General Pharmacology, Institute of Pharmacology, University Medicine Greifswald, D-17487 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utz","family":"Settmacher","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Vascular Surgery, Jena University Hospital, D-07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Lehnert","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7552-2087","authenticated-orcid":false,"given":"Hendrik","family":"Ungefroren","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), and University of L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.7150\/ijbs.15001","article-title":"Pancreatic Cancer Genetics","volume":"12","author":"Amundadottir","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1182\/blood-2013-04-460121","article-title":"Epidemiology of cancer-associated venous thrombosis","volume":"122","author":"Timp","year":"2013","journal-title":"Blood"},{"key":"ref_3","first-page":"9361","article-title":"Cachexia and pancreatic cancer: Are there treatment options?","volume":"20","author":"Mueller","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7150\/ijbs.6.1","article-title":"Smad4-mediated TGF-beta signaling in tumorigenesis","volume":"6","author":"Yang","year":"2010","journal-title":"Int. J. Biol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1126\/science.1164368","article-title":"Core signaling pathways in human pancreatic cancers revealed by global genomic analyses","volume":"321","author":"Jones","year":"2008","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1101\/gad.1475506","article-title":"Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression","volume":"20","author":"Ijichi","year":"2006","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/bph.12544","article-title":"Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease","volume":"171","author":"Hollenberg","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1478-811X-11-86","article-title":"Proteinase-activated receptors (PARs)\u2014Focus on receptor-receptor-interactions and their physiological and pathophysiological impact","volume":"11","author":"Gieseler","year":"2013","journal-title":"Cell Commun. Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16660","DOI":"10.1073\/pnas.1208881109","article-title":"\u03b2-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway","volume":"109","author":"Nichols","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S230","DOI":"10.1038\/sj.bjp.0707491","article-title":"Gastrointestinal roles for proteinase-activated receptors in health and disease","volume":"153","author":"Kawabata","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/MPA.0b013e318201cbc1","article-title":"Proteinase-activated receptor 2 mediates thermal hyperalgesia and is upregulated in a rat model of chronic pancreatitis","volume":"40","author":"Zhang","year":"2011","journal-title":"Pancreas"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/hep.24784","article-title":"Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells","volume":"55","author":"Knight","year":"2012","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1182\/blood-2013-04-460121","article-title":"Epidemiology of cancer-associated venous thrombosis","volume":"122","author":"Timp","year":"2013","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1160\/TH10-12-0789","article-title":"Symptomatic and incidental thromboembolism are both associated with mortality in pancreatic cancer","volume":"106","author":"Menapace","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1093\/humrep\/der125","article-title":"TGF-\u03b21 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6","volume":"26","author":"Saito","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1093\/carcin\/bgp153","article-title":"Met receptor tyrosine kinase transactivation is involved in proteinase-activated receptor-2-mediated hepatocellular carcinoma cell invasion","volume":"30","author":"Kaufmann","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1158\/1541-7786.395.2.7","article-title":"Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis","volume":"2","author":"Shi","year":"2004","journal-title":"Mol. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1158\/0008-5472.CAN-08-0419","article-title":"Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice","volume":"68","author":"Versteeg","year":"2008","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/ijc.23123","article-title":"A small interfering RNA targeting proteinase-activated receptor-2 is effective in suppression of tumor growth in a Panc1 xenograft model","volume":"122","author":"Iwaki","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/MPA.0b013e31829f0b81","article-title":"Proteinase-activated receptors differentially modulate in vitro invasion of human pancreatic adenocarcinoma PANC1 cells in correlation with changes in the expression of CDC42 protein","volume":"43","author":"Segal","year":"2014","journal-title":"Pancreas"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/jso.20420","article-title":"Expression of protease activated receptor-2 (PAR-2) in gastric cancer","volume":"93","author":"Fujimoto","year":"2006","journal-title":"J. Surg. Oncol."},{"key":"ref_22","first-page":"3511","article-title":"Dual role of host Par2 in a murine model of spontaneous metastatic B16 melanoma","volume":"34","author":"Olejar","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.1038\/sj.onc.1210272","article-title":"Dissecting the role of TGF-beta type I receptor\/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function","volume":"26","author":"Schniewind","year":"2007","journal-title":"Oncogene"},{"key":"ref_24","first-page":"149","article-title":"Vicious cycle of TGF-\u03b2 signaling in tumor progression and metastasis","volume":"2","author":"Zhang","year":"2014","journal-title":"Am. J. Clin. Exp. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1478-811X-9-18","article-title":"Interaction of tumor cells with the microenvironment","volume":"9","author":"Ungefroren","year":"2011","journal-title":"Cell Commun. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nrc3603","article-title":"The roles of TGF\u03b2 in the tumour microenvironment","volume":"13","author":"Pickup","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37319","DOI":"10.1074\/jbc.M113.492793","article-title":"Proteinase-activated receptor-2 transactivation of epidermal growth factor receptor and transforming growth factor-\u03b2 receptor signaling pathways contributes to renal fibrosis","volume":"288","author":"Chung","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41095","DOI":"10.18632\/oncotarget.9600","article-title":"Proteinase-activated receptor 2 promotes TGF-\u03b2-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-\u03b2 type I receptor ALK5","volume":"7","author":"Zeeh","year":"2016","journal-title":"Oncotarget"},{"key":"ref_29","unstructured":"Ungefroren, H. (2016). Unpublished work."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nature16064","article-title":"Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer","volume":"527","author":"Zheng","year":"2015","journal-title":"Nature"},{"key":"ref_31","unstructured":"Ungefroren, H. (2015). Unpublished work."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4891","DOI":"10.3390\/ijms11124891","article-title":"Knockdown of snail sensitizes pancreatic cancer cells to chemotherapeutic agents and irradiation","volume":"11","author":"Zhang","year":"2010","journal-title":"Int. J. Mol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1016\/j.cellsig.2016.07.016","article-title":"Negative control of TRAIL-R1 signaling by transforming growth factor \u03b21 in pancreatic tumor cells involves Smad-dependent down regulation of TRAIL-R1","volume":"28","author":"Radke","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.semradonc.2013.05.001","article-title":"Tumors as organs: Biologically augmenting radiation therapy by inhibiting transforming growth factor \u03b2 activity in carcinomas","volume":"23","author":"Du","year":"2013","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_35","first-page":"re5","article-title":"New tricks for an old fox: Impact of TGF\u03b2 on the DNA damage response and genomic stability","volume":"7","author":"Cucinotta","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00018-015-2003-2","article-title":"Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway","volume":"73","author":"Carl","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1007\/s00432-015-1974-6","article-title":"Radiation-induced fibrosis: Mechanisms and implications for therapy","volume":"141","author":"Straub","year":"2015","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12943-016-0538-y","article-title":"Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells\u2014Evidence for a role in hepatocellular carcinoma growth in vivo","volume":"15","author":"Ungefroren","year":"2016","journal-title":"Mol. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00064","DOI":"10.1042\/BSR20130057","article-title":"Activation of blood coagulation in cancer: Implications for tumour progression","volume":"33","author":"Lima","year":"2013","journal-title":"Biosci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10825","DOI":"10.3748\/wjg.v20.i31.10825","article-title":"Novel therapeutic targets for pancreatic cancer","volume":"20","author":"Tang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38527","DOI":"10.1074\/jbc.M104536200","article-title":"Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression","volume":"276","author":"Botella","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_42","first-page":"9","article-title":"Inhibition of TGF\u03b2 signaling and its implication in anticancer treatments","volume":"34","author":"Calone","year":"2012","journal-title":"Exp. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nrd3615","article-title":"Targeting proteinase-activated receptors: Therapeutic potential and challenges","volume":"11","author":"Ramachandran","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7230","DOI":"10.1128\/MCB.23.20.7230-7242.2003","article-title":"Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis","volume":"23","author":"Rebbapragada","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cytogfr.2013.05.003","article-title":"The multiple facets of the TGF-\u03b2 family cytokine growth\/differentiation factor-15\/macrophage inhibitory cytokine-1","volume":"24","author":"Unsicker","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"860","DOI":"10.18632\/oncotarget.6205","article-title":"GDF15 promotes EMT and metastasis in colorectal cancer","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s13539-011-0035-5","article-title":"The role of myostatin in muscle wasting: An overview","volume":"2","author":"Elkina","year":"2011","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1042\/BJ20131151","article-title":"Chitinase-3-like protein 1 protects skeletal muscle from TNF\u03b1-induced inflammation and insulin resistance","volume":"459","author":"Gorgens","year":"2014","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1182\/blood-2013-09-526277","article-title":"Multiple roles of the coagulation protease cascade during virus infection","volume":"123","author":"Antoniak","year":"2014","journal-title":"Blood"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/5\/12\/111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:27:42Z","timestamp":1760210862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/5\/12\/111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,30]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12]]}},"alternative-id":["jcm5120111"],"URL":"https:\/\/doi.org\/10.3390\/jcm5120111","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,30]]}}}