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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,7,26]]},"abstract":"<jats:p>\n                    Autosomal dominant polycystic kidney disease (ADPKD) affects more than 500,000 individuals in the United States alone. In most cases, ADPKD is caused by a loss-of-function mutation in the\n                    <jats:italic>PKD1<\/jats:italic>\n                    gene, which encodes polycystin-1 (PC1). Previous studies reported that PC1 interacts with atypical protein kinase C (aPKC). Here we show that PC1 binds to the \u03b6 isoform of aPKC (PKC\u03b6) and identify two PKC\u03b6 phosphorylation sites on PC1\u2019s C-terminal tail. PKC\u03b6 expression is down-regulated in patients with ADPKD and orthologous and nonorthologous PKD mouse models. We find that the US Food and Drug Administration\u2013approved drug FTY720 restores PKC\u03b6 expression in in\u00a0vitro and in\u00a0vivo models of polycystic kidney disease (PKD) and this correlates with ameliorated disease progression in multiple PKD mouse models. Importantly, we show that FTY720 treatment is less effective in PKC\u03b6 null versions of these PKD mouse models, elucidating a PKC\u03b6-specific mechanism of action that includes inhibiting STAT3 activity and cyst-lining cell proliferation. Taken together, our results reveal that PKC\u03b6 down-regulation is a hallmark of PKD and that its stabilization by FTY720 may represent a therapeutic approach to the treat the disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2121267119","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T14:08:49Z","timestamp":1658498929000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Restoration of atypical protein kinase C \u03b6 function in autosomal dominant polycystic kidney disease ameliorates disease progression"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3257-5883","authenticated-orcid":false,"given":"Masaw","family":"Akbari","sequence":"first","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology; 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and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8441-6131","authenticated-orcid":false,"given":"Sabrina","family":"Vuong","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology; and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9625"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus M.","family":"Rinschen","sequence":"additional","affiliation":[{"name":"Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2399-4610","authenticated-orcid":false,"given":"Jeffrey J.","family":"Talbot","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology; 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