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Here, we show that protein kinase C (PKC) phosphorylates FOXL2 in\u00a0vitro. Two of the four phosphorylation sites, notably Ser101 and Ser107, map to the forkhead DNA\u2010recognition helix. Phosphomimetic substitutions (S\u2009\u2192\u2009D) at these positions (S101D\/S107D) abolish binding to a consensus DNA sequence recognized by FOXL2 and luciferase reporter activation, whereas alanine substitutions are rather neutral. In HeLa cells, the S101D mutant and, to a lesser extent, S107A\/S107D, relocalize at least partially to nucleoli and exhibit increased mobility consistent with reduced DNA engagement. This pattern was recapitulated in stably transduced KGN granulosa cells. RNA\u2010seq of such KGN cells revealed that S101D and a C\u2010terminal truncation (\u0394C) induce a massive loss\u2010of\u2010function (LOF) relative to wild\u2010type (WT) FOXL2. The LOF affects sets of genes involved in pathways central to granulosa physiology including ECM organization, cell migration\/adhesion, and MAPK cascades, whereas S101A is largely WT\u2010like. An analysis of the FOXL2 interactome in the transduced cells by mass spectrometry (MS) showed that S101D loses numerous interactions with TFs and chromatin remodelers, and Pol I\/III regulators such as UBTF and TFIIIC components, while it gains other partners. By contrast, \u0394C retains many of the protein\u2013protein contacts of WT and preferentially loses ribosomal\/TFIII interactions. Together, these data allow us to hypothesize that PKC\u2010dependent phosphorylation within the FOXL2 DNA\u2010recognition helix would underlie a rapid, reversible switch, weakening DNA binding, redirecting subnuclear partitioning, and rewiring protein\u2013protein interactions, thereby reshaping FOXL2\u2010dependent gene regulation in granulosa cells.<\/jats:p>","DOI":"10.1096\/fj.202602528r","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T09:51:06Z","timestamp":1785577866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modification of the Transcription Factor\n                    <scp>FOXL2<\/scp>\n                    at Serines 101 and 107 Disables\n                    <scp>DNA<\/scp>\n                    Binding, Leads to Nucleolar Relocalization, and Rewires Granulosa\u2010Cell 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