{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:16Z","timestamp":1785413536704,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,10]]},"group-title":"Cancer Biology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 DK45729"],"award-info":[{"award-number":["R01 DK45729"]}],"id":[{"id":"https:\/\/ror.org\/00g1g7t14","id-type":"ROR","asserted-by":"publisher"}]},{"name":"UACC Shared Resources and TARGHETS biospecimen core","award":["P30CA062203"],"award-info":[{"award-number":["P30CA062203"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>The multiple endocrine neoplasia type 1 (MEN1)<\/jats:italic>\n                  gene encodes Menin, a nuclear scaffold protein and tumor suppressor that regulates transcription. It is frequently mutated in endocrine neoplasia. MEN1-gastrinomas are aggressive neuroendocrine tumors (NETs) that arise predominantly in the submucosal Brunner\u2019s glands of the duodenum, an organelle rich in extracellular growth factors. Many duodenal NETs retain wild-type\n                  <jats:italic>MEN1<\/jats:italic>\n                  allele and nuclear Menin, suggesting post-translational inactivation of its tumor-suppressor function. The Menin C-terminal domain (CTD) contains a conserved phosphorylation site at Ser487 within the first of three nuclear localization signals (NLS1-3). We hypothesized that extracellular signaling regulates Menin by phosphorylating the CTD at Ser487 blocking its nuclear localization. Using CTD deletion mapping, site-directed mutagenesis, and kinase activation in gastric cell lines, we show that loss of NLS1-3 reduces Menin\u2019s nuclear localization, stability, and repression of\n                  <jats:italic>GASTRIN<\/jats:italic>\n                  . Cell stimulation by epiregulin, forskolin, or phorbol ester induced Menin Ser487 phosphorylation and its nuclear translocation, relieving repression of\n                  <jats:italic>GASTRIN<\/jats:italic>\n                  . The phospho-mimetic S487D mutant remained cytoplasmic and phenocopied CTD deletion of NLS1-3 sustaining de-repression of\n                  <jats:italic>GASTRIN<\/jats:italic>\n                  . These findings showed that Ser487 phosphorylation restricts nuclear accumulation of Menin and functionally links extracellular signaling to post-translational modification of Menin that ultimately contributes to transcriptional derepression and neuroendocrine tumorigenesis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"717082v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.07.717082","type":"posted-content","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T21:40:14Z","timestamp":1775857214000},"source":"Crossref","is-referenced-by-count":0,"title":["Extracellular signalling regulates gastrin transcription through site-specific phosphorylation and nuclear redistribution of Menin"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2135-170X","authenticated-orcid":false,"given":"Uloma B.","family":"Elvis-Offiah","sequence":"first","affiliation":[{"name":"Program in Cancer Biology, University of Arizona Comprehensive Cancer Center, Tucson, AZ, 85724, USA"},{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Abramson Family Cancer Research Institute, Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4862-4691","authenticated-orcid":false,"given":"Xianxin","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Abramson Family Cancer Research Institute, Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-1767","authenticated-orcid":false,"given":"Juanita L.","family":"Merchant","sequence":"additional","affiliation":[{"name":"Program in Cancer Biology, University of Arizona Comprehensive Cancer Center, Tucson, AZ, 85724, USA"},{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041307500654000_2026.04.07.717082v1.1","unstructured":"Cingam SR , Botejue M , Hoilat GJ et al., StatPearls. 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