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Here, we have characterised the most frequent mutation in PKC\u03b2 (D427N), addressing the issue of gain\/loss of function, neomorphic change and assessing the impact of mutation in vivo, in cells, biochemically and structurally. It is concluded that this mutation is a gain-of-function, activating mutation that confers an altered substrate specificity on this protein kinase. In a constitutive knock-in mouse model, this activated allele induces splenomegaly associated with extramedullary haematopoiesis. Pharmacologically, the D427N mutant protein displays poor sensitivity to established PKC\u03b2 inhibitors, necessitating the development of bespoke therapeutics for any ATLL intervention through this target. Such efforts could be guided by the availability of the D427N mutant-ruboxistaurin structure presented here.<\/jats:p>","DOI":"10.1042\/bcj20253384","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T14:15:51Z","timestamp":1760537751000},"page":"1659-1675","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Penetrant PKC\u03b2 mutation in ATLL displays a mixed gain-of-function"],"prefix":"10.1042","volume":"482","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9155-1606","authenticated-orcid":false,"given":"Sophie JL.","family":"Brown","sequence":"first","affiliation":[{"name":"1Protein Phosphorylation Laboratory"},{"name":"2Signalling and Structural Biology Laboratory"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9793-7339","authenticated-orcid":false,"given":"David C.","family":"Briggs","sequence":"additional","affiliation":[{"name":"2Signalling and Structural Biology Laboratory"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4419-5012","authenticated-orcid":false,"given":"Patrick","family":"Costello","sequence":"additional","affiliation":[{"name":"3Signalling and Transcription Laboratory, Francis Crick Institute, London, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-0033","authenticated-orcid":false,"given":"Hiroko","family":"Yaguchi","sequence":"additional","affiliation":[{"name":"4Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2624-3599","authenticated-orcid":false,"given":"Charles RM.","family":"Bangham","sequence":"additional","affiliation":[{"name":"4Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6218-2933","authenticated-orcid":false,"given":"Peter J.","family":"Parker","sequence":"additional","affiliation":[{"name":"1Protein Phosphorylation Laboratory"},{"name":"5School of Cancer and Pharmaceutical Sciences, Guy\u2019s Campus, King\u2019s College London, London, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0975-6325","authenticated-orcid":false,"given":"Neil Q.","family":"McDonald","sequence":"additional","affiliation":[{"name":"2Signalling and Structural Biology Laboratory"},{"name":"6Institute of Structural and Molecular Biology, School of Natural Sciences, Birkbeck College, London, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"2025110509171425000_BCJ-2025-3384C1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1146\/annurev-immunol-042617-053222","article-title":"Human t cell leukemia virus type 1: persistence and pathogenesis","volume":"36","author":"Bangham","year":"2018","journal-title":"Annu. 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