XB-ART-53313
Nat Commun
September 24, 2015;
6
8388.
PTEN regulates cilia through Dishevelled.
Shnitsar I
,
Bashkurov M
,
Masson GR
,
Ogunjimi AA
,
Mosessian S
,
Cabeza EA
,
Hirsch CL
,
Trcka D
,
Gish G
,
Jiao J
,
Wu H
,
Winklbauer R
,
Williams RL
,
Pelletier L
,
Wrana JL
,
Barrios-Rodiles M
.
Abstract
Cilia are hair-like cellular protrusions important in many aspects of eukaryotic biology. For instance, motile cilia enable fluid movement over epithelial surfaces, while primary (sensory) cilia play roles in cellular signalling. The molecular events underlying cilia dynamics, and particularly their disassembly, are not well understood. Phosphatase and tensin homologue (PTEN) is an extensively studied tumour suppressor, thought to primarily act by antagonizing PI3-kinase signalling. Here we demonstrate that PTEN plays an important role in multicilia formation and cilia disassembly by controlling the phosphorylation of Dishevelled (DVL), another ciliogenesis regulator. DVL is a central component of WNT signalling that plays a role during convergent extension movements, which we show here are also regulated by PTEN. Our studies identify a novel protein substrate for PTEN that couples PTEN to regulation of cilia dynamics and WNT signalling, thus advancing our understanding of potential underlying molecular etiologies of PTEN-related pathologies.
PubMed ID: 26399523
PMC ID: PMC4598566
Article link: Nat Commun
Grant support: [+]
MOP-123468 Canadian Institutes of Health Research , MC_U105184308RW Medical Research Council , MOP-130507 Canadian Institutes of Health Research , MOP-53075 Canadian Institutes of Health Research , MC_U105184308 Medical Research Council , MRC_MC_U105184308 Medical Research Council
Species referenced: Xenopus laevis
Genes referenced: dvl1 dvl2 dvl3 pcnt pten tgfbi tns1
Article Images: [+] show captions
References [+] :
Avasthi,
Stages of ciliogenesis and regulation of ciliary length.
2012, Pubmed
Avasthi,
Stages of ciliogenesis and regulation of ciliary length.
2012,
Pubmed
Avasthi, Ciliary regulation: disassembly takes the spotlight. 2013, Pubmed
Barrios-Rodiles, High-throughput mapping of a dynamic signaling network in mammalian cells. 2005, Pubmed
Boutin, A dual role for planar cell polarity genes in ciliated cells. 2014, Pubmed
Choksi, Switching on cilia: transcriptional networks regulating ciliogenesis. 2014, Pubmed
Davidson, Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. 2010, Pubmed
Deblandre, A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos. 1999, Pubmed , Xenbase
Di Cristofano, Pten is essential for embryonic development and tumour suppression. 1998, Pubmed
Drinjakovic, E3 ligase Nedd4 promotes axon branching by downregulating PTEN. 2010, Pubmed , Xenbase
Ferkol, Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. 2012, Pubmed
Franco, PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. 2014, Pubmed
Gao, Dishevelled: The hub of Wnt signaling. 2010, Pubmed
Guirao, Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. 2010, Pubmed
Hirota, Planar polarity of multiciliated ependymal cells involves the anterior migration of basal bodies regulated by non-muscle myosin II. 2010, Pubmed
Hobert, Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly. 2014, Pubmed
Hobert, PTEN hamartoma tumor syndrome: an overview. 2009, Pubmed
Jacoby, INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. 2009, Pubmed
Kawamata, Fine structural aspects of the development and aging of the tracheal epithelium of mice. 1983, Pubmed
Kreis, Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN. 2013, Pubmed
Lee, Identification of a novel Wnt5a-CK1ɛ-Dvl2-Plk1-mediated primary cilia disassembly pathway. 2012, Pubmed
Lesche, Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. 2002, Pubmed
Louvi, Cilia in the CNS: the quiet organelle claims center stage. 2011, Pubmed
Luga, Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. 2012, Pubmed
Maehama, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. 1998, Pubmed
Mahimainathan, Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novel mechanism of action of the phosphatase. 2004, Pubmed
Marshall, Cilia: tuning in to the cell's antenna. 2006, Pubmed
Mashhoon, Crystal structure of a conformation-selective casein kinase-1 inhibitor. 2000, Pubmed
Mirzadeh, Cilia organize ependymal planar polarity. 2010, Pubmed
Mitchell, A positive feedback mechanism governs the polarity and motion of motile cilia. 2007, Pubmed , Xenbase
Mohan, Striated rootlet and nonfilamentous forms of rootletin maintain ciliary function. 2013, Pubmed
Myers, The lipid phosphatase activity of PTEN is critical for its tumor supressor function. 1998, Pubmed
Myers, P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. 1997, Pubmed
Narimatsu, Regulation of planar cell polarity by Smurf ubiquitin ligases. 2009, Pubmed
Novarino, Modeling human disease in humans: the ciliopathies. 2011, Pubmed
Ohtoshi, Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene. 2008, Pubmed
Park, Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. 2008, Pubmed , Xenbase
Pugacheva, HEF1-dependent Aurora A activation induces disassembly of the primary cilium. 2007, Pubmed
Rahdar, A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. 2009, Pubmed
Rawlins, Lung development and repair: contribution of the ciliated lineage. 2007, Pubmed
Rodríguez-Escudero, A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. 2011, Pubmed
Rosivatz, A small molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN). 2007, Pubmed
Satir, Structure and function of mammalian cilia. 2008, Pubmed
Schindelin, Fiji: an open-source platform for biological-image analysis. 2012, Pubmed
Sharma, Ciliary dysfunction in developmental abnormalities and diseases. 2009, Pubmed
Sokol, Analysis of Dishevelled signalling pathways during Xenopus development. 1997, Pubmed , Xenbase
Spassky, Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. 2005, Pubmed
Stambolic, Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. 1998, Pubmed
Stubbs, Radial intercalation of ciliated cells during Xenopus skin development. 2006, Pubmed , Xenbase
Suzuki, High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. 1998, Pubmed
Tamura, PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. 1999, Pubmed
Tibarewal, PTEN protein phosphatase activity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. 2012, Pubmed
Tissir, Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. 2010, Pubmed
Ueno, PTEN is required for the normal progression of gastrulation by repressing cell proliferation after MBT in Xenopus embryos. 2006, Pubmed , Xenbase
Vlahos, A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). 1994, Pubmed
Wallingford, Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. 2001, Pubmed , Xenbase
Wallingford, Planar cell polarity signaling, cilia and polarized ciliary beating. 2010, Pubmed
Yang, The ciliary rootlet maintains long-term stability of sensory cilia. 2005, Pubmed
Avasthi, Ciliary regulation: disassembly takes the spotlight. 2013, Pubmed
Barrios-Rodiles, High-throughput mapping of a dynamic signaling network in mammalian cells. 2005, Pubmed
Boutin, A dual role for planar cell polarity genes in ciliated cells. 2014, Pubmed
Choksi, Switching on cilia: transcriptional networks regulating ciliogenesis. 2014, Pubmed
Davidson, Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. 2010, Pubmed
Deblandre, A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos. 1999, Pubmed , Xenbase
Di Cristofano, Pten is essential for embryonic development and tumour suppression. 1998, Pubmed
Drinjakovic, E3 ligase Nedd4 promotes axon branching by downregulating PTEN. 2010, Pubmed , Xenbase
Ferkol, Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. 2012, Pubmed
Franco, PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. 2014, Pubmed
Gao, Dishevelled: The hub of Wnt signaling. 2010, Pubmed
Guirao, Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. 2010, Pubmed
Hirota, Planar polarity of multiciliated ependymal cells involves the anterior migration of basal bodies regulated by non-muscle myosin II. 2010, Pubmed
Hobert, Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly. 2014, Pubmed
Hobert, PTEN hamartoma tumor syndrome: an overview. 2009, Pubmed
Jacoby, INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. 2009, Pubmed
Kawamata, Fine structural aspects of the development and aging of the tracheal epithelium of mice. 1983, Pubmed
Kreis, Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN. 2013, Pubmed
Lee, Identification of a novel Wnt5a-CK1ɛ-Dvl2-Plk1-mediated primary cilia disassembly pathway. 2012, Pubmed
Lesche, Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. 2002, Pubmed
Louvi, Cilia in the CNS: the quiet organelle claims center stage. 2011, Pubmed
Luga, Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. 2012, Pubmed
Maehama, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. 1998, Pubmed
Mahimainathan, Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novel mechanism of action of the phosphatase. 2004, Pubmed
Marshall, Cilia: tuning in to the cell's antenna. 2006, Pubmed
Mashhoon, Crystal structure of a conformation-selective casein kinase-1 inhibitor. 2000, Pubmed
Mirzadeh, Cilia organize ependymal planar polarity. 2010, Pubmed
Mitchell, A positive feedback mechanism governs the polarity and motion of motile cilia. 2007, Pubmed , Xenbase
Mohan, Striated rootlet and nonfilamentous forms of rootletin maintain ciliary function. 2013, Pubmed
Myers, The lipid phosphatase activity of PTEN is critical for its tumor supressor function. 1998, Pubmed
Myers, P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. 1997, Pubmed
Narimatsu, Regulation of planar cell polarity by Smurf ubiquitin ligases. 2009, Pubmed
Novarino, Modeling human disease in humans: the ciliopathies. 2011, Pubmed
Ohtoshi, Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene. 2008, Pubmed
Park, Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. 2008, Pubmed , Xenbase
Pugacheva, HEF1-dependent Aurora A activation induces disassembly of the primary cilium. 2007, Pubmed
Rahdar, A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. 2009, Pubmed
Rawlins, Lung development and repair: contribution of the ciliated lineage. 2007, Pubmed
Rodríguez-Escudero, A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. 2011, Pubmed
Rosivatz, A small molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN). 2007, Pubmed
Satir, Structure and function of mammalian cilia. 2008, Pubmed
Schindelin, Fiji: an open-source platform for biological-image analysis. 2012, Pubmed
Sharma, Ciliary dysfunction in developmental abnormalities and diseases. 2009, Pubmed
Sokol, Analysis of Dishevelled signalling pathways during Xenopus development. 1997, Pubmed , Xenbase
Spassky, Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. 2005, Pubmed
Stambolic, Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. 1998, Pubmed
Stubbs, Radial intercalation of ciliated cells during Xenopus skin development. 2006, Pubmed , Xenbase
Suzuki, High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. 1998, Pubmed
Tamura, PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. 1999, Pubmed
Tibarewal, PTEN protein phosphatase activity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. 2012, Pubmed
Tissir, Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. 2010, Pubmed
Ueno, PTEN is required for the normal progression of gastrulation by repressing cell proliferation after MBT in Xenopus embryos. 2006, Pubmed , Xenbase
Vlahos, A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). 1994, Pubmed
Wallingford, Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. 2001, Pubmed , Xenbase
Wallingford, Planar cell polarity signaling, cilia and polarized ciliary beating. 2010, Pubmed
Yang, The ciliary rootlet maintains long-term stability of sensory cilia. 2005, Pubmed