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      Actin polymerization controls cilia-mediated signaling

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          Abstract

          Actin polymerization is important to generate primary cilia. Drummond et al. show that upstream actin regulators are necessary for this process by controlling aPKC and Src kinase activity to promote Hedgehog signaling and restrict primary cilia.

          Abstract

          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–aPKC–Gli axis in actin-dependent regulation of primary cilia signaling.

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          The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly.

          Although small GTP-binding proteins of the Rho family have been implicated in signaling to the actin cytoskeleton, the exact nature of the linkage has remained obscure. We describe a novel mechanism that links one Rho family member, Cdc42, to actin polymerization. N-WASP, a ubiquitously expressed Cdc42-interacting protein, is required for Cdc42-stimulated actin polymerization in Xenopus egg extracts. The C terminus of N-WASP binds to the Arp2/3 complex and dramatically stimulates its ability to nucleate actin polymerization. Although full-length N-WASP is less effective, its activity can be greatly enhanced by Cdc42 and phosphatidylinositol (4,5) bisphosphate. Therefore, N-WASP and the Arp2/3 complex comprise a core mechanism that directly connects signal transduction pathways to the stimulation of actin polymerization.
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            Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis.

            Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.
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              Dual and opposing roles of primary cilia in medulloblastoma development

              Recent work has shown that primary cilia are essential for Hh signaling during mammalian development1–9. It is also known that aberrant Hedgehog (Hh) signaling can lead to cancer10, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children11,12. The primary cilium and Hh signaling are required for GNPs proliferation8,13–16. We asked whether primary cilia in GNPs play a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma growth when this tumor was driven by a constitutively active Smoothened (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active Gli2, a downstream transcription factor. Thus, primary cilia are required for, or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, presence or absence of cilia were associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling, but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                03 September 2018
                : 217
                : 9
                : 3255-3266
                Affiliations
                [1 ]Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA
                [2 ]Department of Dermatology, University of California, Irvine, Irvine, CA
                [3 ]Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA
                [4 ]Department of Dermatology, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA
                Author notes
                Correspondence to Scott X. Atwood: satwood@ 123456uci.edu
                Anthony E. Oro: oro@ 123456stanford.edu
                Author information
                http://orcid.org/0000-0001-5452-4529
                http://orcid.org/0000-0002-1729-1444
                http://orcid.org/0000-0001-7407-9792
                Article
                201703196
                10.1083/jcb.201703196
                6122990
                29945904
                766581b4-8c5c-4ccc-ad0a-b7e8c43602ef
                © 2018 Drummond et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 27 March 2017
                : 29 March 2018
                : 31 May 2018
                Funding
                Funded by: National Science Foundation, DOI https://doi.org/10.13039/100000001;
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: R00CA176847
                Award ID: R01ARO52785
                Funded by: University California, Irvine, DOI https://doi.org/10.13039/100008476;
                Categories
                Research Articles
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                Cell biology
                Cell biology

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