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Its activation at centrosomes and spindle microtubules is promoted by CEP192, TACC3 and TPX2, and counteracted by protein phosphatase 6 (PP6), which dephosphorylates the Aurora A T-loop. PP6 forms three holoenzymes defined by regulatory subunits PPP6R1\u2013R3, yet how these confer substrate recognition and regulation is poorly understood. Here, we identify a phenylalanine-rich motif (A-box), present in PPP6R2 and PPP6R3 but absent from PPP6R1, that binds a surface on Aurora A overlapping those used by CEP192, TPX2 and TACC3. Mutation of A-box phenylalanine residues disrupts Aurora A binding and T-loop dephosphorylation, elevating spindle-associated Aurora A activity, and enlarging mitotic spindles. PPP6R2 additionally contains a unique PLK1-docking site downstream of its A-box, explaining how PLK1 competes with Aurora A for PPP6R2 and thereby suppresses PP6 activity towards Aurora A. Together, these findings show that PP6 regulatory subunits mimic Aurora A activators to direct dephosphorylation, and reveal how competing interactions regulate PP6 in mitosis.<\/jats:p>","DOI":"10.1038\/s44318-026-00923-9","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:16:50Z","timestamp":1792599410000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activator mimicry by PP6 regulatory subunits directs Aurora A dephosphorylation in mitosis"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-5361","authenticated-orcid":false,"given":"Tomoaki","family":"Sobajima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gege","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josip","family":"Ahel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Poser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8344-0500","authenticated-orcid":false,"given":"Ulrike","family":"Gruneberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-253X","authenticated-orcid":false,"given":"Francis A","family":"Barr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"923_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, Ronneberger O, Willmore L, Ballard AJ, Bambrick J et al (2024) Accurate structure prediction of biomolecular interactions with AlphaFold 3. 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