{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:26:25Z","timestamp":1791030385511,"version":"4.1.0"},"reference-count":71,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2004,7,12]],"date-time":"2004-07-12T00:00:00Z","timestamp":1089590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2004,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The RET\/PTC3 oncogene is a genetically rearranged and constitutively activated tyrosine kinase receptor that is common in papillary thyroid cancer. Because RET\/PTC3 is chronically overexpressed in these thyroid cancer cells, and RET\/PTC3\u2010expressing tumors are associated with overactivity of tyrosine kinase signaling pathways and a more aggressive clinical course, we questioned whether chronic RET\/PTC3 expression enhances cellular responses to thyroid mitogens in vitro. We stably transfected FRTL\u20105 cells with the <jats:italic>RET<\/jats:italic>\/<jats:italic>PTC3<\/jats:italic> gene; transfected and control cell lines were cultured without insulin, TSH, or serum. Thymidine incorporation into DNA was enhanced in the RET\/PTC3 cells, but transformation was not observed. RET\/PTC3 cells demonstrated higher basal and insulin\u2010stimulated levels of activated Akt, both of which were reduced by LY294002, a PI3 kinase inhibitor, but not PD98059, a MEK inhibitor. By contrast, mitogen activated protein kinase (MAP kinase) was only minimally activated in RET\/PTC3 cells before and after stimulation. Consistent with preferential activation of PI3 kinase, increased levels of total and phosphorylated IRS2 protein, relative activation of PDK\u20101, and enhanced IRS2\u2010p85 interactions were identified in RET\/PTC3\u2010expressing cells. RET\/PTC3 cells were also sensitized to insulin\u2010induced thymidine incorporation; this effect was blocked by PI3 kinase (LY294002) rather than MEK 1\/2 (PD98059) inhibitors. In summary, we have demonstrated that RET\/PTC3 expression enhances basal and insulin\u2010stimulated DNA synthesis through PI3 kinase, cooperatively activates Akt with insulin via PI3 kinase, and preferentially activates the Akt rather than MAP kinase pathway in FRTL\u20105 cells. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/mc.20042","type":"journal-article","created":{"date-parts":[[2004,7,13]],"date-time":"2004-07-13T07:03:51Z","timestamp":1089702231000},"page":"98-107","source":"Crossref","is-referenced-by-count":41,"title":["Chronic expression of RET\/PTC 3 enhances basal and insulin\u2010stimulated PI3 kinase\/AKT signaling and increases IRS\u20102 expression in FRTL\u20105 thyroid cells"],"prefix":"10.1002","volume":"41","author":[{"given":"Eri","family":"Miyagi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Braga\u2010Basaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasily","family":"Vasko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D.","family":"Burman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sissy","family":"Jhiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoyasu","family":"Saji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew 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