{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T01:53:52Z","timestamp":1774317232853,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Transglutaminase 2 (TG2) is an important mesothelioma cancer cell survival protein. However, the mechanism whereby TG2 maintains mesothelioma cell survival is not well understood. We present studies showing that TG2 drives hepatocyte growth factor (HGF)\u2010dependent MET receptor signaling to maintain the aggressive mesothelioma cancer phenotype. TG2 increases HGF and MET messenger RNA and protein levels to enhance MET signaling. TG2 inactivation reduces MET tyrosine kinase activity to reduce cancer cell spheroid formation, invasion and migration. We also confirm that HGF\/MET signaling is a biologically important mediator of TG2 action. Reducing MET level using genetic methods or treatment with MET inhibitors reduces spheroid formation, invasion and migration and this is associated with reduced MEK1\/2 and ERK1\/2. In addition, MEK1\/2 and ERK1\/2 inhibitors suppress the cancer phenotype. Moreover, MET knockout mesothelioma cells form 10\u2010fold smaller tumors compared to wild\u2010type cells and these tumors display reduced MET, MEK1\/2, and ERK1\/2 activity. These findings suggest that TG2 maintains HGF and MET levels in cultured mesothelioma cells and tumors to drive HGF\/MET, MEK1\/2, and ERK1\/2 signaling to maintain the aggressive mesothelioma cancer phenotype.<\/jats:p>","DOI":"10.1002\/mc.23399","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T13:18:40Z","timestamp":1648041520000},"page":"537-548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transglutaminase 2 enhances hepatocyte growth factor signaling to drive the mesothelioma cancer cell phenotype"],"prefix":"10.1002","volume":"61","author":[{"given":"Warren","family":"Naselsky","sequence":"first","affiliation":[{"name":"Division of Thoracic Oncology, Department of Surgery University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gautam","family":"Adhikary","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suruchi","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geraldine","family":"Ezeka","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Xu","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph S","family":"Friedberg","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, Department of Surgery University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-4779","authenticated-orcid":false,"given":"Richard L.","family":"Eckert","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Department of Dermatology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Department of Reproductive Biology University of Maryland School of Medicine  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-014-2029-1"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdl060"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.11.136"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26130"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.2288"},{"issue":"6","key":"e_1_2_10_7_1","first-page":"1909","article-title":"Tissue transglutaminase promotes or suppresses tumors depending on cell context","volume":"29","author":"Chhabra A","year":"2009","journal-title":"Anticancer Res"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020701"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr3085"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22986"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00019.2013"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(02)02182-5"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08346.x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22375"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3890"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2032"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1107"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-011-1167-9"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210035"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr3034"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgm280"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013390"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1257"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.429"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758834011422556"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.12.014"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines2040327"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052825"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1362-2"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2010.108"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.205245"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers9120169"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0477"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6107(98)00056-X"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0183"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.06.029"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.507"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22943"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0685-T"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.30"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1998.176"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(19980413)76:2<240::AID-IJC12>3.0.CO;2-G"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2000.1445"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004320050171"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-1191"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0206OC"},{"issue":"13","key":"e_1_2_10_47_1","first-page":"3539","article-title":"Microarray analysis and RNA silencing link fra\u20101 to cd44 and c\u2010met expression in mesothelioma","volume":"63","author":"Ramos\u2010Nino ME","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208744"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.1.247"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22687"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604544103"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.08.103"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.11.005"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0282OC"},{"issue":"2","key":"e_1_2_10_55_1","first-page":"809","article-title":"Suppression of pro\u2010metastasis phenotypes expression in malignant pleural mesothelioma by the PI3K inhibitor LY294002 or the MEK inhibitor UO126","volume":"26","author":"Cole GW","year":"2006","journal-title":"Anticancer Res"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25763"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-9-314"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.23399","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mc.23399","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.23399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T12:50:31Z","timestamp":1692881431000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.23399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":56,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["10.1002\/mc.23399"],"URL":"https:\/\/doi.org\/10.1002\/mc.23399","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]},"assertion":[{"value":"2021-12-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}