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The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKC\u03b4 resulting in PIT1\/CDKN2A-ARF\/p53-apoptosis pathway activation. AIP-deficiency blocks RET\/caspase-3\/PKC\u03b4 activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic\n                    <jats:italic>AIP<\/jats:italic>\n                    variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific\n                    <jats:italic>Aip<\/jats:italic>\n                    -knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without\n                    <jats:italic>AIP<\/jats:italic>\n                    mutation abundantly express GDNF, but\n                    <jats:italic>AIP<\/jats:italic>\n                    -mutated tissues have less\n                    <jats:italic>CDKN2A-ARF<\/jats:italic>\n                    expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for\n                    <jats:italic>AIP<\/jats:italic>\n                    -related tumours.\n                  <\/jats:p>","DOI":"10.1038\/s41388-021-02009-8","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T11:11:16Z","timestamp":1632913876000},"page":"6354-6368","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas"],"prefix":"10.1038","volume":"40","author":[{"given":"Angela R.","family":"Garcia-Rendueles","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Chenlo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Oroz-Gonjar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Solomou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5001-2697","authenticated-orcid":false,"given":"Anisha","family":"Mistry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayka","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Gaston-Massuet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9208-2418","authenticated-orcid":false,"given":"Montserrat","family":"Garcia-Lavandeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihara","family":"Perez-Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Suarez-Fari\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Pradilla-Dieste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Dieguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Mehlen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4101-9432","authenticated-orcid":false,"given":"M\u00e1rta","family":"Korbonits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1500-4058","authenticated-orcid":false,"given":"Clara V.","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"2009_CR1","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/jcp.21295","volume":"215","author":"A Solloso","year":"2008","unstructured":"Solloso A, Barreiro L, Seoane R, Nogueira E, Canibano C, Alvarez CV, et al. 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