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One such mutant, p53\n                    <jats:sup>R273H<\/jats:sup>\n                    , is known to promote the activation of the PI3K\/AKT pathway, but the underlying mechanism is unclear. Here, we demonstrated a direct interaction between p53\n                    <jats:sup>R273H<\/jats:sup>\n                    and 3\u2010phosphoinositide\u2010dependent protein kinase 1 (PDPK1), an upstream kinase of AKT. Interestingly, this interaction was unique to p53\n                    <jats:sup>R273H<\/jats:sup>\n                    , as it was not seen with wild\u2010type p53 or other hotspot mutants such as p53\n                    <jats:sup>R175H<\/jats:sup>\n                    and p53\n                    <jats:sup>R248W<\/jats:sup>\n                    . Mechanistically, our\n                    <jats:italic>in silico<\/jats:italic>\n                    analysis revealed that the R273H mutation exposed a hydrophobic region within the p53\n                    <jats:sup>R273H<\/jats:sup>\n                    DNA\u2010binding domain (DBD), facilitating PDPK1 binding. This binding disrupted PDPK1 homodimerization, a known inhibitory mechanism of PDPK1 activity. In contrast, the PDPK1\u2010binding deficient mutant p53\n                    <jats:sup>F270A\/R273H<\/jats:sup>\n                    did not disrupt PDPK1 homodimerization. We propose that p53\n                    <jats:sup>R273H<\/jats:sup>\n                    promotes AKT phosphorylation, potentially by enhancing PDPK1 homodimer dissociation. Supporting this, the small molecule PRIMA\u20101\n                    <jats:sup>Met<\/jats:sup>\n                    disrupted the p53\n                    <jats:sup>R273H<\/jats:sup>\n                    \u2010PDPK1 interaction, resulting in reduced AKT phosphorylation. These findings highlight a new gain\u2010of\u2010function role of p53\n                    <jats:sup>R273H<\/jats:sup>\n                    , suggesting that targeting the p53\n                    <jats:sup>R273H<\/jats:sup>\n                    \u2010PDPK1 interaction with PRIMA\u20101\n                    <jats:sup>Met<\/jats:sup>\n                    could dampen AKT phosphorylation in p53\n                    <jats:sup>R273H<\/jats:sup>\n                    \u2010expressing cancers.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70341","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:37:23Z","timestamp":1790678243000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mutant\n                    <scp>\n                      p53\n                      <sup>R273H<\/sup>\n                    <\/scp>\n                    disrupts\n                    <scp>PDPK1<\/scp>\n                    homodimerization and contributes to\n                    <scp>PDPK1<\/scp>\n                    activation"],"prefix":"10.1002","author":[{"given":"Mei Chee","family":"Lim","sequence":"first","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin Kunyao","family":"Guo","sequence":"additional","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Itahana","sequence":"additional","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasaraghavan","family":"Kannan","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute, Agency for Science Technology, and Research 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