{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T02:59:58Z","timestamp":1789095598093,"version":"build-2803163510"},"reference-count":46,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                    <jats:p\/>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Rearranged during transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point mutations gives rise to the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand-independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of a ligand. These mutations cause intrinsic biochemical changes in the RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Furthermore, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to the differences in tumour progression and disease aggressiveness.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/erc-24-0187","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:39:53Z","timestamp":1729690793000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":6,"title":["Cellular mechanisms of RET receptor dysfunction in multiple endocrine neoplasia 2"],"prefix":"10.1530","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6146-3485","authenticated-orcid":true,"given":"Timothy J","family":"Walker","sequence":"first","affiliation":[{"name":"Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen\u2019s University , , ,","place":["Kingston, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9308-8245","authenticated-orcid":true,"given":"Lois M","family":"Mulligan","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen\u2019s University , , ,","place":["Kingston, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"2026070905401084400_bib1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/jmg.2007.053959","article-title":"Hirschsprung disease, associated syndromes and genetics: a review","volume":"45","author":"Amiel","year":"2007","journal-title":"J Med 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