{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:22:48Z","timestamp":1762251768064},"reference-count":59,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,8]]},"abstract":"<jats:p>Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (<jats:italic>RET<\/jats:italic>) proto-oncogene. <jats:italic>RET<\/jats:italic> encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS\u2013RAF\u2013ERK1\/2, PIK3\u2013AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line <jats:italic>RET<\/jats:italic> variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the <jats:italic>RET<\/jats:italic> variants and measured the number of NIH3T3 transformation <jats:italic>foci<\/jats:italic> and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1\/2, STAT1, STAT3, and TCF4), and the extent of ERK1\/2 inhibition on sorafenib treatment. We found that <jats:italic>RET<\/jats:italic> variants Arg886Trp and Glu511Lys have shown increased <jats:italic>in vitro<\/jats:italic> transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type <jats:italic>RET<\/jats:italic> (<jats:italic>RET<\/jats:italic>-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1\/2 activation respectively, that was significantly higher than that observed for <jats:italic>RET<\/jats:italic>-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for <jats:italic>RET<\/jats:italic> Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold in <jats:italic>RET<\/jats:italic>-WT respectively). The three <jats:italic>RET<\/jats:italic> variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens.<\/jats:p>","DOI":"10.1530\/erc-10-0258","type":"journal-article","created":{"date-parts":[[2011,5,7]],"date-time":"2011-05-07T04:54:49Z","timestamp":1304744089000},"page":"401-412","update-policy":"http:\/\/dx.doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":11,"title":["In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp"],"prefix":"10.1530","volume":"18","author":[{"given":"Hugo","family":"Prazeres","sequence":"first","affiliation":[]},{"given":"Joana P","family":"Couto","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Vinagre","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Torres","sequence":"additional","affiliation":[]},{"given":"Vitor","family":"Trovisco","sequence":"additional","affiliation":[]},{"given":"Teresa C","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"Sobrinho-Sim\u00f5es","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[]}],"member":"416","reference":[{"issue":"5","key":"1_10843723","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1006\/mcne.1999.0754","volume":"13","author":"Airaksinen","year":"1999","journal-title":"Molecular and cellular neurosciences","ISSN":"http:\/\/id.crossref.org\/issn\/1044-7431","issn-type":"print"},{"issue":"1","key":"2_17142977","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/ajmg.10399","volume":"110","author":"Anti\u00a0\u00a0olo","year":"2002","journal-title":"American journal of medical genetics","ISSN":"http:\/\/id.crossref.org\/issn\/0148-7299","issn-type":"print"},{"issue":"4-5","key":"3_19286293","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/j.cytogfr.2005.05.010","volume":"16","author":"Arighi","year":"2005","journal-title":"Cytokine &amp; 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