{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:30:58Z","timestamp":1790796658003,"version":"4.1.0"},"reference-count":45,"publisher":"Rockefeller University Press","issue":"9","license":[{"start":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T00:00:00Z","timestamp":1574208000000},"content-version":"vor","delay-in-days":512,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T00:00:00Z","timestamp":1551571200000},"content-version":"vor","delay-in-days":250,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00CA176847"],"award-info":[{"award-number":["R00CA176847"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01ARO52785"],"award-info":[{"award-number":["R01ARO52785"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008476","name":"University California, Irvine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,9,3]]},"abstract":"<jats:p>Primary cilia are polarized organelles that allow detection of extracellular signals such as Hedgehog (Hh). How the cytoskeleton supporting the cilium generates and maintains a structure that finely tunes cellular response remains unclear. Here, we find that regulation of actin polymerization controls primary cilia and Hh signaling. Disrupting actin polymerization, or knockdown of N-WASp\/Arp3, increases ciliation frequency, axoneme length, and Hh signaling. Cdc42, a potent actin regulator, recruits both atypical protein pinase C iota\/lambda (aPKC) and Missing-in-Metastasis (MIM) to the basal body to maintain actin polymerization and restrict axoneme length. Transcriptome analysis implicates the Src pathway as a major aPKC effector. aPKC promotes whereas MIM antagonizes Src activity to maintain proper levels of primary cilia, actin polymerization, and Hh signaling. Hh pathway activation requires Smoothened-, Gli-, and Gli1-specific activation by aPKC. Surprisingly, longer axonemes can amplify Hh signaling, except when aPKC is disrupted, reinforcing the importance of the Cdc42\u2013aPKC\u2013Gli axis in actin-dependent regulation of primary cilia signaling.<\/jats:p>","DOI":"10.1083\/jcb.201703196","type":"journal-article","created":{"date-parts":[[2018,6,26]],"date-time":"2018-06-26T17:15:29Z","timestamp":1530033329000},"page":"3255-3266","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":89,"title":["Actin polymerization controls cilia-mediated signaling"],"prefix":"10.1083","volume":"217","author":[{"given":"Michael L.","family":"Drummond","sequence":"first","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-4529","authenticated-orcid":true,"given":"Mischa","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Tarapore","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuyen T.L.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baina J.","family":"Barouni","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Cruz","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1729-1444","authenticated-orcid":true,"given":"Kevin C.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Oro","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7407-9792","authenticated-orcid":true,"given":"Scott X.","family":"Atwood","sequence":"additional","affiliation":[{"name":"Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 1"},{"name":"Department of Dermatology, University of California, Irvine, Irvine, CA 2"},{"name":"Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2018,6,26]]},"reference":[{"key":"2023072515360736700_bib1","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.devcel.2013.12.003","article-title":"Making the connection: ciliary adhesion complexes anchor basal bodies to the actin cytoskeleton","volume":"28","author":"Antoniades","year":"2014","journal-title":"Dev. Cell."},{"key":"2023072515360736700_bib2","doi-asserted-by":"publisher","first-page":"3200","DOI":"10.1242\/jcs.014902","article-title":"Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6 aPKC","volume":"120","author":"Atwood","year":"2007","journal-title":"J. Cell Sci."},{"key":"2023072515360736700_bib3","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1083\/jcb.201207140","article-title":"Hedgehog pathway inhibition and the race against tumor evolution","volume":"199","author":"Atwood","year":"2012","journal-title":"J. Cell Biol."},{"key":"2023072515360736700_bib4","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nature11889","article-title":"GLI activation by atypical protein kinase C \u03b9\/\u03bb regulates the growth of basal cell carcinomas","volume":"494","author":"Atwood","year":"2013","journal-title":"Nature."},{"key":"2023072515360736700_bib5","doi-asserted-by":"publisher","first-page":"S30","DOI":"10.1016\/j.diff.2011.11.015","article-title":"Stages of ciliogenesis and regulation of ciliary length","volume":"83","author":"Avasthi","year":"2012","journal-title":"Differentiation."},{"key":"2023072515360736700_bib6","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/nm.4368","article-title":"Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas","volume":"23","author":"Bal","year":"2017","journal-title":"Nat. Med."},{"key":"2023072515360736700_bib7","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.devcel.2010.07.009","article-title":"MIM and cortactin antagonism regulates ciliogenesis and hedgehog signaling","volume":"19","author":"Bershteyn","year":"2010","journal-title":"Dev. Cell."},{"key":"2023072515360736700_bib8","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1124\/mol.115.099457","article-title":"Protein Kinase C (PKC)\u03b6 Pseudosubstrate Inhibitor Peptide Promiscuously Binds PKC Family Isoforms and Disrupts Conventional PKC Targeting and Translocation","volume":"88","author":"Bogard","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"2023072515360736700_bib9","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/nrm3598","article-title":"The mechanisms of Hedgehog signalling and its roles in development and disease","volume":"14","author":"Briscoe","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072515360736700_bib10","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinformatics."},{"key":"2023072515360736700_bib11","doi-asserted-by":"publisher","first-page":"16520","DOI":"10.1073\/pnas.0603533103","article-title":"Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly","volume":"103","author":"Chen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072515360736700_bib12","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1681\/ASN.2012121236","article-title":"Cdc42 deficiency causes ciliary abnormalities and cystic kidneys","volume":"24","author":"Choi","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"2023072515360736700_bib13","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1016\/j.jmb.2016.03.003","article-title":"Molecular Control of Atypical Protein Kinase C: Tipping the Balance between Self-Renewal and Differentiation","volume":"428","author":"Drummond","year":"2016","journal-title":"J. Mol. Biol."},{"key":"2023072515360736700_bib14","doi-asserted-by":"publisher","first-page":"4293","DOI":"10.1242\/jcs.164509","article-title":"Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development","volume":"128","author":"Elias","year":"2015","journal-title":"J. Cell Sci."},{"key":"2023072515360736700_bib15","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1083\/jcb.101.1.96","article-title":"Evidence for an involvement of actin in the positioning and motility of centrosomes","volume":"101","author":"Euteneuer","year":"1985","journal-title":"J. Cell Biol."},{"key":"2023072515360736700_bib16","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1016\/j.cub.2004.08.025","article-title":"Polarity proteins control ciliogenesis via kinesin motor interactions","volume":"14","author":"Fan","year":"2004","journal-title":"Curr. Biol."},{"key":"2023072515360736700_bib17","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1083\/jcb.201009001","article-title":"A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells","volume":"193","author":"Francis","year":"2011","journal-title":"J. Cell Biol."},{"key":"2023072515360736700_bib18","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nrg2774","article-title":"The primary cilium: a signalling centre during vertebrate development","volume":"11","author":"Goetz","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2023072515360736700_bib19","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1038\/nm.2020","article-title":"Dual and opposing roles of primary cilia in medulloblastoma development","volume":"15","author":"Han","year":"2009","journal-title":"Nat. Med."},{"key":"2023072515360736700_bib20","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.chembiol.2013.03.019","article-title":"Small molecules CK-666 and CK-869 inhibit actin-related protein 2\/3 complex by blocking an activating conformational change","volume":"20","author":"Hetrick","year":"2013","journal-title":"Chem. Biol."},{"key":"2023072515360736700_bib21","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.cell.2004.06.027","article-title":"Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex","volume":"118","author":"Ho","year":"2004","journal-title":"Cell."},{"key":"2023072515360736700_bib22","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.devcel.2004.05.003","article-title":"Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis","volume":"6","author":"Hutterer","year":"2004","journal-title":"Dev. Cell."},{"key":"2023072515360736700_bib23","doi-asserted-by":"publisher","first-page":"E6","DOI":"10.3390\/cells5010006","article-title":"Cellular Mechanisms of Ciliary Length Control","volume":"5","author":"Keeling","year":"2016","journal-title":"Cells."},{"key":"2023072515360736700_bib24","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.ceb.2013.04.011","article-title":"Assembling a primary cilium","volume":"25","author":"Kim","year":"2013","journal-title":"Curr. Opin. Cell Biol."},{"key":"2023072515360736700_bib25","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1038\/nature08895","article-title":"Functional genomic screen for modulators of ciliogenesis and cilium length","volume":"464","author":"Kim","year":"2010","journal-title":"Nature."},{"key":"2023072515360736700_bib26","doi-asserted-by":"publisher","first-page":"2459","DOI":"10.1093\/emboj\/18.9.2459","article-title":"Src family kinases are required for integrin but not PDGFR signal transduction","volume":"18","author":"Klinghoffer","year":"1999","journal-title":"EMBO J."},{"key":"2023072515360736700_bib27","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.15252\/embr.201643846","article-title":"The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia","volume":"18","author":"Kohli","year":"2017","journal-title":"EMBO Rep."},{"key":"2023072515360736700_bib28","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2023072515360736700_bib29","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/1471-2121-9-49","article-title":"Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines","volume":"9","author":"Lipinski","year":"2008","journal-title":"BMC Cell Biol."},{"key":"2023072515360736700_bib30","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.cell.2010.02.040","article-title":"aPKC phosphorylation of Bazooka defines the apical\/lateral border in Drosophila epithelial cells","volume":"141","author":"Morais-de-S\u00e1","year":"2010","journal-title":"Cell."},{"key":"2023072515360736700_bib31","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.cell.2016.11.036","article-title":"An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling","volume":"168","author":"Nager","year":"2017","journal-title":"Cell."},{"key":"2023072515360736700_bib32","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/nrm3775","article-title":"Organization and execution of the epithelial polarity programme","volume":"15","author":"Rodriguez-Boulan","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072515360736700_bib33","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S0092-8674(00)80732-1","article-title":"The interaction between N-WASP and the Arp2\/3 complex links Cdc42-dependent signals to actin assembly","volume":"97","author":"Rohatgi","year":"1999","journal-title":"Cell."},{"key":"2023072515360736700_bib34","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1083\/jcb.200709111","article-title":"Par3 functions in the biogenesis of the primary cilium in polarized epithelial cells","volume":"179","author":"Sfakianos","year":"2007","journal-title":"J. Cell Biol."},{"key":"2023072515360736700_bib35","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1242\/jcs.3.2.207","article-title":"Reconstructions of centriole formation and ciliogenesis in mammalian lungs","volume":"3","author":"Sorokin","year":"1968","journal-title":"J. Cell Sci."},{"key":"2023072515360736700_bib36","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1042\/BJ20151013","article-title":"Protein kinase C\u03b6 exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation","volume":"473","author":"Tobias","year":"2016","journal-title":"Biochem. J."},{"key":"2023072515360736700_bib37","doi-asserted-by":"publisher","first-page":"21845","DOI":"10.1074\/jbc.M115.676221","article-title":"Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62","volume":"290","author":"Tsai","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2023072515360736700_bib38","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.devcel.2005.12.014","article-title":"Divergence of hedgehog signal transduction mechanism between Drosophila and mammals","volume":"10","author":"Varjosalo","year":"2006","journal-title":"Dev. Cell."},{"key":"2023072515360736700_bib39","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.cell.2008.07.049","article-title":"Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization","volume":"135","author":"Wirtz-Peitz","year":"2008","journal-title":"Cell."},{"key":"2023072515360736700_bib40","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1038\/nm.2011","article-title":"Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis","volume":"15","author":"Wong","year":"2009","journal-title":"Nat. Med."},{"key":"2023072515360736700_bib41","first-page":"e4344","article-title":"Rapid genetic analysis of epithelial-mesenchymal signaling during hair regeneration","volume":"72","author":"Woo","year":"2013","journal-title":"J. Vis. Exp."},{"key":"2023072515360736700_bib42","doi-asserted-by":"publisher","first-page":"8414","DOI":"10.1128\/MCB.21.24.8414-8427.2001","article-title":"Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C\u2019s via a src kinase pathway","volume":"21","author":"Wooten","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"2023072515360736700_bib43","doi-asserted-by":"publisher","first-page":"12879","DOI":"10.1074\/jbc.M112.357244","article-title":"Cellular pharmacology of protein kinase M\u03b6 (PKM\u03b6) contrasts with its in vitro profile: implications for PKM\u03b6 as a mediator of memory","volume":"287","author":"Wu-Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023072515360736700_bib44","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1146\/annurev-genet-111212-133243","article-title":"Expanding horizons: ciliary proteins reach beyond cilia","volume":"47","author":"Yuan","year":"2013","journal-title":"Annu. Rev. Genet."},{"key":"2023072515360736700_bib45","doi-asserted-by":"publisher","first-page":"22469","DOI":"10.1074\/jbc.M111.238469","article-title":"The small GTPase Cdc42 is necessary for primary ciliogenesis in renal tubular epithelial cells","volume":"286","author":"Zuo","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/217\/9\/3255\/1601937\/jcb_201703196.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/217\/9\/3255\/1601937\/jcb_201703196.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T17:15:53Z","timestamp":1690305353000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/217\/9\/3255\/120854\/Actin-polymerization-controls-cilia-mediated"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,26]]},"references-count":45,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,9,3]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.201703196","relation":{},"ISSN":["0021-9525","1540-8140"],"issn-type":[{"value":"0021-9525","type":"print"},{"value":"1540-8140","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,26]]}}}