{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:43:08Z","timestamp":1781898188480,"version":"3.54.5"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM122523 1R01NS120725 T32 GM007752"],"award-info":[{"award-number":["R35 GM122523 1R01NS120725 T32 GM007752"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Protein kinase C (PKC) isozymes transduce myriad signals within the cell in response to the generation of second messengers from membrane phospholipids. The conventional isozyme PKC\u03b3 reversibly binds Ca<jats:sup>2+<\/jats:sup> and diacylglycerol, which leads to an open, active conformation. PKC\u03b3 expression is typically restricted to neurons, but evidence for its expression in certain cancers has emerged. PKC isozymes have been labeled as oncogenes since the discovery that they bind tumor-promoting phorbol esters, however, studies of cancer-associated PKC mutations and clinical trial data showing that PKC inhibitors have worsened patient survival have reframed PKC as a tumor suppressor. Aberrant expression of PKC\u03b3 in certain cancers suggests a role outside the brain, although whether PKC\u03b3 also acts as a tumor suppressor remains to be established. On the other hand, PKC\u03b3 variants associated with spinocerebellar ataxia type 14 (SCA14), a neurodegenerative disorder characterized by Purkinje cell degeneration, enhance basal activity while preventing phorbol ester-mediated degradation. Although the basis for SCA14 Purkinje cell degeneration remains unknown, studies have revealed how altered PKC\u03b3 activity rewires cerebellar signaling to drive SCA14. Importantly, enhanced basal activity of SCA14-associated mutants inversely correlates with age of onset, supporting that enhanced PKC\u03b3 activity drives SCA14. Thus, PKC\u03b3 activity should likely be inhibited in SCA14, whereas restoring PKC activity should be the goal in cancer therapies. This review describes how PKC\u03b3 activity can be lost or gained in disease and the overarching need for a PKC structure as a powerful tool to predict the effect of PKC\u03b3 mutations in disease.<\/jats:p>","DOI":"10.3389\/fcell.2022.929510","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T05:44:13Z","timestamp":1655790253000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Two Sides of the Same Coin: Protein Kinase C \u03b3 in Cancer and Neurodegeneration"],"prefix":"10.3389","volume":"10","author":[{"given":"Caila A.","family":"Pilo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C.","family":"Newton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13262","DOI":"10.1074\/jbc.M112.349753","article-title":"Peptidyl-prolyl Isomerase Pin1 Controls Down-Regulation of Conventional Protein Kinase C Isozymes","volume":"287","author":"Abrahamsen","year":"2012","journal-title":"J. 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