{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:45:54Z","timestamp":1787946354494,"version":"build-2784847793"},"reference-count":51,"publisher":"The Royal Society","issue":"1957","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010438","name":"Francis Crick Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","award":["CC2068"],"award-info":[{"award-number":["CC2068"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CC2068"],"award-info":[{"award-number":["CC2068"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["CC2068"],"award-info":[{"award-number":["CC2068"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100019154","name":"Barts Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019154","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019154","name":"Barts Cancer Institute","doi-asserted-by":"publisher","award":["C355\/A25137"],"award-info":[{"award-number":["C355\/A25137"]}],"id":[{"id":"10.13039\/501100019154","id-type":"DOI","asserted-by":"publisher"}]},{"name":"City of London Centre","award":["C7893\/A26233"],"award-info":[{"award-number":["C7893\/A26233"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There is a growing literature describing non-catalytic functions of active protein kinases, reflecting the importance of these properties in the kinase repertoire. Here, we discuss recent work in this area relating to the kinase activity-independent oncogenic action of protein kinase C (PKC) alpha and draw parallels in relation with another PKC family member. We go on to illustrate some of the challenges in unpicking these non-catalytic properties with reference to the wider kinome, illustrating the issue that the wrong loss-of-function mutation may mislead. Finally, we comment on the opportunities these deeper insights bring.<\/jats:p>\n                  <jats:p>This article is part of the discussion meeting issue \u2018Epidermal growth factor receptor after 40 years\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2024.0496","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:08:47Z","timestamp":1787814527000},"source":"Crossref","is-referenced-by-count":1,"title":["Lessons in conformational signalling: non-catalytic functions of protein kinase C isozymes"],"prefix":"10.1098","volume":"381","author":[{"given":"Angus","family":"Cameron","sequence":"first","affiliation":[{"name":"Barts Cancer Institute, Queen Mary University of London 1 , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Cobbaut","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Calleja","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"McDonald","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6218-2933","authenticated-orcid":false,"given":"Peter","family":"Parker","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 2 , London, UK"},{"name":"Faculty of Life Sciences & Medicine, King's College London 3 , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026082703084442100_RSTB20240496C1","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.bbapap.2009.10.017","article-title":"Defining the conserved internal architecture of a protein kinase","volume":"1804","author":"Kornev","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"2026082703084442100_RSTB20240496C2","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification","volume":"9","author":"Hanks","year":"1995","journal-title":"FASEB J."},{"key":"2026082703084442100_RSTB20240496C3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1158\/0008-5472.CAN-17-2291","article-title":"New perspectives, opportunities, and challenges in exploring the human protein kinome","volume":"78","author":"Wilson","year":"2018","journal-title":"Cancer Res."},{"key":"2026082703084442100_RSTB20240496C4","doi-asserted-by":"crossref","first-page":"925","DOI":"10.3390\/cells12060925","article-title":"Mapping the protein kinome: current strategy and future direction","volume":"12","author":"Hou","year":"2023","journal-title":"Cells"},{"key":"2026082703084442100_RSTB20240496C5","doi-asserted-by":"crossref","first-page":"eaat9797","DOI":"10.1126\/scisignal.aat9797","article-title":"Emerging concepts in pseudoenzyme classification, evolution, and signaling","volume":"12","author":"Ribeiro","year":"2019","journal-title":"Sci. Signal."},{"key":"2026082703084442100_RSTB20240496C6","doi-asserted-by":"crossref","first-page":"eaav3810","DOI":"10.1126\/scisignal.aav3810","article-title":"Tracing the origin and evolution of pseudokinases across the tree of life","volume":"12","author":"Kwon","year":"2019","journal-title":"Sci. Signal."},{"key":"2026082703084442100_RSTB20240496C7","doi-asserted-by":"crossref","first-page":"100705","DOI":"10.1016\/j.jbc.2021.100705","article-title":"There's more to death than life: non-catalytic functions in kinase and pseudokinase signaling","volume":"296","author":"Mace","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2026082703084442100_RSTB20240496C8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1055\/s-0029-1246223","article-title":"Chordoid glioma: ten years of a low-grade tumor with high morbidity","volume":"20","author":"Desouza","year":"2010","journal-title":"Skull Base."},{"key":"2026082703084442100_RSTB20240496C9","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/s41467-018-02826-8","article-title":"A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle","volume":"9","author":"Goode","year":"2018","journal-title":"Nat. Commun."},{"key":"2026082703084442100_RSTB20240496C10","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1038\/s41467-018-04622-w","article-title":"A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas","volume":"9","author":"Rosenberg","year":"2018","journal-title":"Nat. Commun."},{"key":"2026082703084442100_RSTB20240496C11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41568-020-00310-4","article-title":"Equivocal, explicit and emergent actions of PKC isoforms in cancer","volume":"21","author":"Parker","year":"2021","journal-title":"Nat. Rev. Cancer."},{"key":"2026082703084442100_RSTB20240496C12","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/pro.5560030203","article-title":"cAMP-dependent protein kinase: crystallographic insights into substrate recognition and phosphotransfer","volume":"3","author":"Madhusudan","year":"1994","journal-title":"Protein Sci."},{"key":"2026082703084442100_RSTB20240496C13","doi-asserted-by":"crossref","first-page":"6955","DOI":"10.1158\/0008-5472.CAN-06-0268","article-title":"Protein kinase C alpha but not PKCzeta suppresses intestinal tumor formation in ApcMin\/+ mice","volume":"66","author":"Oster","year":"2006","journal-title":"Cancer Res."},{"key":"2026082703084442100_RSTB20240496C14","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1042\/bj3330631","article-title":"The broad specificity of dominant inhibitory protein kinase C mutants infers a common step in phosphorylation","volume":"333","author":"Garcia-Paramio","year":"1998","journal-title":"Biochem. J."},{"key":"2026082703084442100_RSTB20240496C15","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/nsmb.1606","article-title":"PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity","volume":"16","author":"Cameron","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026082703084442100_RSTB20240496C16","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/ijc.23560","article-title":"PKC alpha protein, but not kinase activity, is critical for glioma cell proliferation and survival","volume":"123","author":"Cameron","year":"2008","journal-title":"Int. J. Cancer"},{"key":"2026082703084442100_RSTB20240496C17","doi-asserted-by":"crossref","DOI":"10.1101\/2025.05.28.656646","article-title":"The penetrant chordoid glioma PRKCA mutation is an oncogenic gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice","author":"Calleja","year":"2025"},{"key":"2026082703084442100_RSTB20240496C18","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.molcel.2005.06.027","article-title":"The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription","volume":"19","author":"Jang","year":"2005","journal-title":"Mol. Cell."},{"key":"2026082703084442100_RSTB20240496C19","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.1111\/febs.16580","article-title":"BRD4 and MYC: power couple in transcription and disease","volume":"290","author":"Kotekar","year":"2023","journal-title":"FEBS J."},{"key":"2026082703084442100_RSTB20240496C20","doi-asserted-by":"crossref","first-page":"e60191","DOI":"10.7554\/eLife.60191","article-title":"MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1","volume":"10","author":"Popay","year":"2021","journal-title":"eLife"},{"key":"2026082703084442100_RSTB20240496C21","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1038\/onc.2015.416","article-title":"Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif","volume":"35","author":"Thomas","year":"2016","journal-title":"Oncogene"},{"key":"2026082703084442100_RSTB20240496C22","doi-asserted-by":"crossref","first-page":"100516","DOI":"10.1016\/j.jbc.2021.100516","article-title":"PKC\u03b1-mediated phosphorylation of the diacylglycerol kinase \u03b6 MARCKS domain switches cell migration modes by regulating interactions with Rac1 and RhoA","volume":"296","author":"Ard","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2026082703084442100_RSTB20240496C23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41580-022-00465-y","article-title":"Apical-basal polarity and the control of epithelial form and function","volume":"23","author":"Buckley","year":"2022","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"2026082703084442100_RSTB20240496C24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.yexcr.2014.08.008","article-title":"Mammalian aPKC\/Par polarity complex-mediated regulation of epithelial division orientation and cell fate","volume":"328","author":"Vorhagen","year":"2014","journal-title":"Exp. Cell Res."},{"key":"2026082703084442100_RSTB20240496C25","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/s41594-025-01506-8","article-title":"A PAR6\u2013aPKC\u2013LGL structure reveals how LGL antagonizes aPKC","volume":"32","author":"St Johnston","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026082703084442100_RSTB20240496C26","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/s41594-024-01425-0","article-title":"Capture, mutual inhibition, and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl","volume":"32","author":"Earl","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026082703084442100_RSTB20240496C27","doi-asserted-by":"crossref","first-page":"ra82","DOI":"10.1126\/scisignal.2004068","article-title":"A cancer-associated mutation in atypical protein kinase C\u00a0iota occurs in a substrate-specific recruitment motif","volume":"6","author":"Linch","year":"2013","journal-title":"Sci. Signal."},{"key":"2026082703084442100_RSTB20240496C28","doi-asserted-by":"crossref","DOI":"10.21203\/rs.3.rs-5588596\/v1","article-title":"An efficient off-membrane switch: Par6 facilitates processive phosphorylation of Lgl's serine sites via a dynamic interaction with aPKC","author":"Almagor","year":"2025"},{"key":"2026082703084442100_RSTB20240496C29","doi-asserted-by":"crossref","first-page":"4931","DOI":"10.1021\/bi500748w","article-title":"Ordered multisite phosphorylation of lethal giant larvae by atypical protein kinase C","volume":"53","author":"Graybill","year":"2014","journal-title":"Biochemistry"},{"key":"2026082703084442100_RSTB20240496C30","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1242\/dev.01645","article-title":"aPKC, Crumbs3, and Lgl2 control apicobasal polarity in early vertebrate development","volume":"132","author":"Chalmers","year":"2005","journal-title":"Development"},{"key":"2026082703084442100_RSTB20240496C31","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1016\/j.cub.2008.09.029","article-title":"Cdc42, Par6, and aPKC regulate Arp2\/3-mediated endocytosis to control local adherens junction stability","volume":"18","author":"Georgiou","year":"2008","journal-title":"Curr. Biol."},{"key":"2026082703084442100_RSTB20240496C32","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1083\/jcb.201611061","article-title":"Cdc42 regulates junctional actin but not cell polarization in the Caenorhabditis elegans epidermis","volume":"216","author":"Zilberman","year":"2017","journal-title":"J. Cell Biol."},{"key":"2026082703084442100_RSTB20240496C33","doi-asserted-by":"crossref","first-page":"e201903031","DOI":"10.1083\/jcb.201903031","article-title":"A polybasic domain in aPKC mediates Par6-dependent control of membrane targeting and kinase activity","volume":"219","author":"Dong","year":"2020","journal-title":"J. Cell Biol."},{"key":"2026082703084442100_RSTB20240496C34","doi-asserted-by":"crossref","first-page":"104847","DOI":"10.1016\/j.jbc.2023.104847","article-title":"Control of atypical PKCiota membrane dissociation by tyrosine phosphorylation within a PB1-C1 interdomain interface","volume":"299","author":"Cobbaut","year":"2023","journal-title":"J Biol. Chem."},{"key":"2026082703084442100_RSTB20240496C35","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1042\/BCJ20230390","article-title":"Into the fold: advances in understanding aPKC membrane dynamics","volume":"480","author":"Cobbaut","year":"2023","journal-title":"Biochem. J."},{"key":"2026082703084442100_RSTB20240496C36","doi-asserted-by":"crossref","first-page":"e202112143","DOI":"10.1083\/jcb.202112143","article-title":"Cooperative regulation of C1-domain membrane recruitment polarizes atypical protein kinase C","volume":"222","author":"Jones","year":"2023","journal-title":"J. Cell Biol."},{"key":"2026082703084442100_RSTB20240496C37","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/S0960-9822(03)00244-6","article-title":"Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity","volume":"13","author":"Yamanaka","year":"2003","journal-title":"Curr. Biol."},{"key":"2026082703084442100_RSTB20240496C38","doi-asserted-by":"crossref","first-page":"10804","DOI":"10.1073\/pnas.1821514116","article-title":"Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2","volume":"116","author":"Almagor","year":"2019","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026082703084442100_RSTB20240496C39","doi-asserted-by":"crossref","first-page":"903","DOI":"10.12688\/f1000research.14427.1","article-title":"aPKC: the kinase that phosphorylates cell polarity","volume":"7","author":"Hong","year":"2018","journal-title":"F1000Res"},{"key":"2026082703084442100_RSTB20240496C40","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.str.2015.10.020","article-title":"Structural basis for the non-catalytic functions of protein kinases","volume":"24","author":"Kung","year":"2016","journal-title":"Structure"},{"key":"2026082703084442100_RSTB20240496C41","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1478-811X-9-23","article-title":"The secret life of kinases: functions beyond catalysis","volume":"9","author":"Rauch","year":"2011","journal-title":"Cell Commun. Signal."},{"key":"2026082703084442100_RSTB20240496C42","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1146\/annurev-biochem-060614-034402","article-title":"A structural perspective on the regulation of the epidermal growth factor receptor","volume":"84","author":"Kovacs","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"2026082703084442100_RSTB20240496C43","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell signaling by receptor tyrosine kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"},{"key":"2026082703084442100_RSTB20240496C44","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ccr.2008.12.005","article-title":"Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma","volume":"15","author":"Otto","year":"2009","journal-title":"Cancer Cell"},{"key":"2026082703084442100_RSTB20240496C45","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ccr.2014.07.015","article-title":"Drugging MYCN through an allosteric transition in Aurora kinase A","volume":"26","author":"Gustafson","year":"2014","journal-title":"Cancer Cell"},{"key":"2026082703084442100_RSTB20240496C46","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.semcdb.2020.06.014","article-title":"RIPK protein kinase family: atypical lives of typical kinases","volume":"109","author":"Cuny","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"2026082703084442100_RSTB20240496C47","doi-asserted-by":"crossref","first-page":"5476","DOI":"10.4049\/jimmunol.1400499","article-title":"Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice","volume":"192","author":"Berger","year":"2014","journal-title":"J. Immunol."},{"key":"2026082703084442100_RSTB20240496C48","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1126\/science.1249361","article-title":"Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis","volume":"343","author":"Newton","year":"2014","journal-title":"Science"},{"key":"2026082703084442100_RSTB20240496C49","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.molcel.2014.10.021","article-title":"RIP3 induces apoptosis independent of pronecrotic kinase activity","volume":"56","author":"Mandal","year":"2014","journal-title":"Mol. Cell."},{"key":"2026082703084442100_RSTB20240496C50","doi-asserted-by":"crossref","first-page":"eado1252","DOI":"10.1126\/scisignal.ado1252","article-title":"Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines","volume":"18","author":"Eisen","year":"2025","journal-title":"Sci. Signal."},{"key":"2026082703084442100_RSTB20240496C51","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1016\/j.immuni.2024.04.025","article-title":"A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death","volume":"57","author":"Mannion","year":"2024","journal-title":"Immunity"}],"container-title":["Philosophical Transactions of the Royal Society B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/rstb\/article-pdf\/doi\/10.1098\/rstb.2024.0496\/6162280\/rstb.2024.0496.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/royalsocietypublishing.org\/rstb\/article-pdf\/doi\/10.1098\/rstb.2024.0496\/6162280\/rstb.2024.0496.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:08:54Z","timestamp":1787814534000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/rstb\/article\/381\/1957\/20240496\/483094\/Lessons-in-conformational-signalling-non-catalytic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":51,"journal-issue":{"issue":"1957","published-online":{"date-parts":[[2026,8,27]]},"published-print":{"date-parts":[[2026,8,27]]}},"URL":"https:\/\/doi.org\/10.1098\/rstb.2024.0496","relation":{},"ISSN":["0962-8436","1471-2970"],"issn-type":[{"value":"0962-8436","type":"print"},{"value":"1471-2970","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"article-number":"20240496"}}