{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:35:15Z","timestamp":1785418515248,"version":"3.56.0"},"reference-count":27,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Merit Review","doi-asserted-by":"publisher","award":["1 I01BX004931-01A2"],"award-info":[{"award-number":["1 I01BX004931-01A2"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1 I01BX004931-01A2"],"award-info":[{"award-number":["1 I01BX004931-01A2"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Basic Laboratory Research & Development Research Career Scientist Award","doi-asserted-by":"publisher","award":["IK6BX004015"],"award-info":[{"award-number":["IK6BX004015"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine Strategic Research Initiative","award":["SRIG"],"award-info":[{"award-number":["SRIG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>CARP-1, a perinuclear phospho-protein, is a biphasic regulator of cell survival and apoptosis signaling. We previously found that UV cross-linking of proteins from HeLa cervical cancer cells resulted in STAT3 interacting with the CARP-1 (614\u2013638) peptide. Mutagenesis and co-IP-WB experiments revealed that CARP-1 interacts with a 40-amino-acid epitope from positions 441\u2013480 (CE Epitope) located in the STAT3 DNA-binding domain. Overexpression of mutant STAT3 with in-frame deletion of the CE epitope (Gst-STAT3 (\u0394CE) mutant), but not Gst-STAT3 (WT), failed to translocate to the nucleus in IL-6-treated cells. The small GTPase p21Rac1 interacts with and regulates STAT3 activation and nuclear translocation. Here we report the interaction of p21Rac1 with the CE epitope of STAT3 and the CARP-1 (600\u2013650) region, suggesting that CARP-1 is part of a dynamic STAT3-p21Rac1 complex that functions in STAT3 activation and nuclear translocation. Expression of a STAT3 (\u0394CE) mutant abolished STAT3 Y705 phosphorylation in cells that were treated with EGF or IL-6. Fine mapping revealed that scrambling the CE epitope peptide or a small peptide from positions 456\u2013465 within the CE epitope resulted in abrogation of STAT3 Y705 phosphorylation by IL-6. Moreover, STAT3 phosphorylation by EGF or IL-6 was diminished in multiple CARP-1 null cancer cells. Importantly, incubation of a TAT-tagged STAT3 (454\u2013467) peptide but not its scrambled version resulted in a reduction in STAT3 Y705 phosphorylation by IL-6\/EGF. Taken together, our data demonstrates that the STAT3 CE epitope interacts with CARP-1 and p21Rac1, harbors novel sequences that activate STAT3 and promotes its nuclear translocation by IL-6\/EGF.<\/jats:p>","DOI":"10.3390\/cells15090755","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Mechanism of STAT3 Activation by Oncogenic Signaling"],"prefix":"10.3390","volume":"15","author":[{"given":"Magesh","family":"Muthu","sequence":"first","affiliation":[{"name":"John D. Dingell V.A. Medical Center, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaganathan","family":"Venkatesh","sequence":"additional","affiliation":[{"name":"John D. Dingell V.A. Medical Center, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaladhar B.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8611-9923","authenticated-orcid":false,"given":"Arun K.","family":"Rishi","sequence":"additional","affiliation":[{"name":"John D. Dingell V.A. Medical Center, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1002\/mco2.124","article-title":"STAT3 pathway in cancers: Past, present, and future","volume":"3","author":"Wang","year":"2022","journal-title":"Medcomm"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41568-018-0090-8","article-title":"Therapeutically exploiting STAT3 activity in cancer-using tissue repair as a road map","volume":"19","author":"Huynh","year":"2019","journal-title":"Nat. Rev. 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