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The field has been framed by a sequence\u2010based definition of a pseudokinase, where the absence of one or more of the three critical catalytic residues required for phosphoryl transfer in conventional protein kinases has allowed their classification. As a result, pseudokinases have been defined by their dissimilarity to active kinases, meaning they are the outcasts or black sheep of the kinome. Pseudokinases are prevalent in nature, accounting for 10% or more of the kinase complement throughout phyla, and have been reported to mediate diverse functions in controlling the activities of other enzymes allosterically, mediating signaling complex assembly, serving as conformational switches and as negative regulators of signaling flux. Here, we review our current understanding of the varied pseudokinase functions as a window toward understanding non\u2010catalytic functions of conventional protein kinases, the challenges associated with defining pseudokinases\u2014especially in cases where cryptic catalytic activities have been reported\u2014and the emergence of pseudokinases as pharmacological targets.<\/jats:p>","DOI":"10.1002\/iub.70125","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:46:28Z","timestamp":1787805988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Black Sheep: Pseudokinases Bucking the Trend to Reveal Non\u2010Catalytic Kinase Functions"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0195-3949","authenticated-orcid":false,"given":"James M.","family":"Murphy","sequence":"first","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville Victoria Australia"},{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Monash University  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5129-641X","authenticated-orcid":false,"given":"Natalia","family":"Jura","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute University of California San Francisco  San Francisco California USA"},{"name":"Department of Cellular and Molecular Pharmacology University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-9537","authenticated-orcid":false,"given":"Peter D.","family":"Mace","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biomedical Sciences University 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