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STAT5-mediated gene regulation involves tyrosine phosphorylation at cytokine receptors and subsequent nuclear import. We studied STAT5 nucleocytoplasmic shuttling via live-cell imaging of fluorescent mutants in STAT5\n                    <jats:sup>-\/-<\/jats:sup>\n                    HeLa EpoR cells. Unexpectedly, STAT5 mutants lacking the transactivation domain (TAD) were retained in the cytoplasm following Epo stimulation. Building upon this, we identified a 12-amino-acid stretch in the TAD sufficient to restore nuclear translocation. Further analysis revealed two residues within this 12\u2011amino\u2011acid stretch, D754 and D758, to be essential for nuclear import of phosphorylated full-length STAT5. Importantly, a single intact TAD in the STAT5 dimer is sufficient for nuclear import. Our findings reveal a unique role of the TAD in STAT5 nuclear trafficking distinct from other STATs, providing new mechanistic insight and potential targets for therapeutic intervention in STAT5-driven disease such as myeloproliferative neoplasms and leukemia.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10898-2","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:04:33Z","timestamp":1790420673000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unexpected functional role of the transactivation domain for nuclear import of STAT5"],"prefix":"10.1038","volume":"9","author":[{"given":"Sabrina","family":"Ernst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merith","family":"Borgen-M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"K\u00fcster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Schurse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-7693","authenticated-orcid":false,"given":"Gerhard","family":"M\u00fcller-Newen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"10898_CR1","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1039\/B606246F","volume":"2","author":"CP Lim","year":"2006","unstructured":"Lim, C. 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