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This salvage mechanism involves methylation-dependent activation of the IRES-\n                      <jats:italic>trans<\/jats:italic>\n                      -acting factor (ITAF) hnRNP A1 by PRMT5. However, the upstream regulators of this PRMT5\/hnRNP A1 axis remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To identify upstream effectors, a yeast two-hybrid screen using PRMT5 revealed PKA-C\u03b1 as an interacting partner. This interaction was validated via coimmunoprecipitation and colocalization in GBM cells. Functional relevance was assessed using biochemical, genetic, and pharmacological approaches to modulate PKA activity and examine effects on PRMT5 phosphorylation, hnRNP A1 methylation, IRES activity, and mTOR inhibitor resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PKA associated with PRMT5 and was activated in response to mTOR inhibition, correlating with increased cyclin D1 and c-myc mRNA IRES activity. PKA knockdown or inhibition attenuated IRES activation following mTOR inhibitor exposure. PRMT5 was phosphorylated at ser15 by PKA and this modification was required for PRMT5\u2013hnRNP A1 interaction and downstream arginine methylation at residues R218\/R225. A non-phosphorylatable PRMT5 S15A mutant failed to bind hnRNP A1, whereas a phosphomimetic S15E variant enhanced this association. PKA activation increased hnRNP A1 methylation, while combined inhibition of PKA and mTOR reduced GBM cell viability, suppressed IRES-mediated translation, and induced apoptosis both in vitro and in intracranial xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings identify a PKA\/PRMT5\/hnRNP A1 signaling axis that promotes IRES-dependent translation and contributes to mTOR inhibitor resistance in GBM. Dual inhibition of PKA and mTOR may represent a promising therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05564-w","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:31:32Z","timestamp":1780659092000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PKA signaling modulates PRMT5\/hnRNP A1-mediated IRES translation and dictates responses to mTOR inhibition in glioblastoma"],"prefix":"10.1007","volume":"178","author":[{"given":"Sunil","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Benavides-Serrato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn T.","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Nishimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Gera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"5564_CR1","doi-asserted-by":"publisher","unstructured":"Price M, Ballard C, Benedetti J, Neff C, Cioffi G, Waite KA, Kruchko C, Barnholtz-Sloan JS, Ostrom QT (2024) CBTRUS statistical report: primary Brain and other central nervous System tumors diagnosed in the United States in 2017\u20132021. 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