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  • Original Article
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A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma

Oncogene volume 36, pages 5969–5984 (2017)Cite this article

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Abstract

Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3. INPP5E promotes SHH signaling during embryonic development via PtdIns(4,5)P2 hydrolysis at cilia, that in turn regulates the cilia recruitment of the SHH suppressor GPR161. However, the role INPP5E plays in cancer is unknown and the contribution of PI3-kinase signaling to cilia function is little characterized. Here, we reveal INPP5E promotes SHH signaling in SHH medulloblastoma by negatively regulating a cilia-compartmentalized PI3-kinase signaling axis that maintains primary cilia on tumor cells. Conditional deletion of Inpp5e in a murine model of constitutively active Smoothened-driven medulloblastoma slowed tumor progression, suppressed cell proliferation, reduced SHH signaling and promoted tumor cell cilia loss. PtdIns(3,4,5)P3, its effector pAKT and the target pGSK3β, which when non-phosphorylated promotes cilia assembly/stability, localized to tumor cell cilia. The number of PtdIns(3,4,5)P3/pAKT/pGSK3β-positive cilia was increased in cultured Inpp5e-null tumor cells relative to controls. PI3-kinase inhibition or expression of wild-type, but not catalytically inactive HA-INPP5E partially rescued cilia loss in Inpp5e-null tumor cells in vitro. INPP5E mRNA and copy number were reduced in human SHH medulloblastoma compared to other molecular subtypes and consistent with the murine model, reduced INPP5E was associated with improved overall survival. Therefore our study identifies a compartmentalized PtdIns(3,4,5)P3/AKT/GSK3β signaling axis at cilia in SHH-dependent medulloblastoma that is regulated by INPP5E to maintain tumor cell cilia, promote SHH signaling and thereby medulloblastoma progression.

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References

  1. Schüller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 2008; 14: 123–134.

    PubMed  PubMed Central  Google Scholar 

  2. Yang Z, Ellis T, Markant SL, Read T, Kessler JD, Bourboulas M et al. Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 2008; 14: 135–145.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L et al. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361: 1173–1178.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011; 29: 1408–1414.

    PubMed  Google Scholar 

  5. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW . Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers 2016; 8: pii E22.

    PubMed  Google Scholar 

  6. Avasthi P, Marshall WF . Stages of ciliogenesis and regulation of ciliary length. Differentiation 2012; 83: S30–S42.

    CAS  PubMed  Google Scholar 

  7. Spassky N, Han YG, Aguilar A, Strehl L, Besse L, Laclef C et al. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol 2008; 317: 246–259.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Han Y, Kim HJ, Dlugosz AA, Ellison DW, Gilbertson RJ, Alvarez-Buylla A . Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 2009; 15: 1062–1065.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Barakat MT, Humke EW, Scott MP . Kif3a is necessary for initiation and maintenance of medulloblastoma. Carcinogenesis 2013; 34: 1382–1392.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Fruman DA, Rommel C . PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Vanhaesebroeck B, Stephens L, Hawkins P . PI3K signaling: the path to discovery and understanding. Nat Rev Mol Cell Biol 2012; 13: 195–203.

    CAS  PubMed  Google Scholar 

  12. Kool M, Jones DTW, Jäger N, Northcott PA, Pugh TJ, Hovestadt V et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 2014; 25: 393–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Metcalfe C, Alicke B, Crow A, Lamoureux M, Dijkgraaf GJP, Peale F et al. PTEN loss mitigates the response of medulloblastoma to Hedgehog pathway inhibition. Cancer Res 2013; 73: 7034–7342.

    CAS  PubMed  Google Scholar 

  14. Castellino RC, Barwick BG, Schniederjan M, Buss MC, Becher O, Hambardzumyan D et al. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma. PLoS One 2010; 5: e10849.

    PubMed  PubMed Central  Google Scholar 

  15. Conduit SE, Dyson JM, Mitchell CA . Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies. FEBS lett 2012; 586: 2846–2857.

    CAS  PubMed  Google Scholar 

  16. Luo N, Kumar A, Conwell M, Weinreb RN, Anderson R, Sun Y . Compensatory role of inositol 5-phosphatase INPP5B to OCRL in primary cilia formation in oculocerebrorenal syndrome of lowe. PLoS One 2013; 8: e66727.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hamze-Komaiha O, Sarr S, Arlot-Bonnemains Y, Samuel D, Gassama-Diagne A . SHIP2 regulates lumen generation, cell division, and ciliogenesis through the control of basolateral to apical lumen localization of aurora A and HEF 1. Cell Rep 2016; 17: 2738–2752.

    CAS  PubMed  Google Scholar 

  18. Kong AM, Speed CJ, O'Malley CJ, Layton MJ, Meehan T, Loveland KL et al. Cloning and characterization of a 72-kDa Inositol-polyphosphate 5-phosphatase localized to the golgi network. J Biol Chem 2000; 275: 24052–24064.

    CAS  PubMed  Google Scholar 

  19. Kisseleva MV, Wilson MP, Majerus PW . The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate 5-phosphatase. J Biol Chem 2000; 275: 20110–20116.

    CAS  PubMed  Google Scholar 

  20. Kisseleva MV, Cao L, Majerus PW . Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits akt/protein kinase b phosphorylation and leads to apoptotic cell death. J Biol Chem 2002; 277: 6266–6272.

    CAS  PubMed  Google Scholar 

  21. Hakim S, Dyson JM, Feeney SJ, Davies EM, Sriratana A, Koenig MN et al. Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling. Hum Mol Genet 2016; 25: 2295–2313.

    CAS  PubMed  Google Scholar 

  22. Jacoby M, Cox JJ, Gayral S, Hampshire DJ, Ayub M, Blockmans M et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 2009; 41: 1027–1031.

    CAS  PubMed  Google Scholar 

  23. Dyson JM, Conduit SE, Feeney SJ, Hakim S, DiTommaso T, Fulcher AJ et al. INPP5E regulates phosphoinositide-dependent cilia transition zone function. J Cell Biol 2017; 216: 247–263.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Garcia-Gonzalo FR, Phua SC, Roberson EC, Garcia G, Abedin M, Schurmans S et al. Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev Cell 2015; 34: 400–409.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chávez M, Ena S, Van Sande J, de Kerchove d'Exaerde A, Schurmans S, Schiffmann SN . Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev Cell 2015; 34: 338–350.

    PubMed  Google Scholar 

  26. Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 2009; 41: 1032–1036.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ge X, Milenkovic L, Suyama K, Hartl T, Purzner T, Winans A et al. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. eLife 2015; 4: eLife 07068.

    Google Scholar 

  28. Julian E, Hallahan A, Wainwright B . RBP-J is not required for granule neuron progenitor development and medulloblastoma initiated by Hedgehog pathway activation in the external germinal layer. Neural Dev 2010; 15: 537.

    Google Scholar 

  29. Frick A, Grammel D, Schmidt F, Poschl J, Priller M, Pagella P et al. Proper cerebellar development requires expression of beta1-integrin in Bergmann glia, but not in granule neurons. Glia 2012; 60: 820–832.

    PubMed  Google Scholar 

  30. Joo W, Hippenmeyer S, Luo L . Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling. Science 2014; 346: 626–629.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim JC, Cook MN, Carey MR, Shen C, Regehr WG, Dymecki SM . Linking genetically defined neurons to behavior through a broadly applicable silencing allele. Neuron 2009; 63: 305–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee EY, Ji H, Ouyang Z, Zhou B, Ma W, Vokes SA et al. Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis. Proc Natl Acad Sci U S A 2010; 107: 9736–9741.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pei Y, Brun SN, Markant SL, Lento W, Gibson P, Taketo MM et al. WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum. Development 2012; 139: 1724–1733.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hou C, Ding L, Zhang J, Jin Y, Sun C, Li Z et al. Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice. Dev Biol 2014; 395: 167–181.

    CAS  PubMed  Google Scholar 

  35. Lorenz A, Deutschmann M, Ahlfeld J, Prix C, Koch A, Smits R et al. Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors. Mol Cell Biol 2011; 31: 3326–3338.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Otero JJ, Kalaszczynska I, Michowski W, Wong M, Gygli PE, Gokozan HN et al. Cerebellar cortical lamination and foliation require cyclin A2. Dev Biol 2014; 385: 328–339.

    CAS  PubMed  Google Scholar 

  37. Machold R, Fishell G . Math1 Is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 2005; 48: 17–24.

    CAS  PubMed  Google Scholar 

  38. Heine VM, Priller M, Ling J, Rowitch DH, Schüller U . Dexamethasone destabilizes Nmyc to inhibit the growth of hedgehog-associated medulloblastoma. Cancer Res 2010; 70: 5220–5225.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Pöschl J, Lorenz A, Hartmann W, von Bueren AO, Kool M, Li S et al. Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans. Oncogene 2011; 30: 4721–4730.

    PubMed  PubMed Central  Google Scholar 

  40. Crowther AJ, Gama V, Bevilacqua A, Chang SX, Yuan H, Deshmukh M et al. Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma. J Neurosci 2013; 33: 18098–18108.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Crowther AJ, Ocasio JK, Fang F, Meidinger J, Wu J, Deal AM et al. Radiation sensitivity in a preclinical mouse model of medulloblastoma relies on the function of the intrinsic apoptotic pathway. Cancer Res 2016; 76: 3211–3223.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lam C, Xie J, To K, Ng H, Lee K, Yuen N et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 1999; 18: 833–836.

    CAS  PubMed  Google Scholar 

  43. Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 2009; 15: 135–147.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L et al. Quiescent Sox2+ cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell 2014; 26: 33–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002; 297: 1559–1561.

    CAS  PubMed  Google Scholar 

  46. Chen JK, Taipale J, Young KE, Maiti T, Beachy PA . Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 2002; 99: 14071–14076.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hatton BA, Knoepfler PS, Kenney AM, Rowitch DH, de Alborán IM, Olson JM et al. N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth. Cancer Res 2006; 66: 8655–8661.

    CAS  PubMed  Google Scholar 

  48. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DYR, Reiter JF . Vertebrate smoothened functions at the primary cilium. Nature 2005; 437: 1018–1021.

    CAS  PubMed  Google Scholar 

  49. Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ et al. The ciliary G-Protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. Cell 2013; 152: 210–223.

    CAS  PubMed  Google Scholar 

  50. Pal K, Hwang SH, Somatilaka B, Badgandi H, Jackson PK, DeFea K et al. Smoothened determines β-arrestin–mediated removal of the G protein–coupled receptor Gpr161 from the primary cilium. J Cell Biol 2016; 212: 861–875.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Park J, Lee N, Kavoussi A, Seo JT, Kim CH, Moon SJ . Ciliary phosphoinositide regulates ciliary protein trafficking in drosophila. Cell Rep 2015; 13: 2808–2816.

    CAS  PubMed  Google Scholar 

  52. Jensen VL, Li C, Bowie RV, Clarke L, Mohan S, Blacque OE et al. Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signaling proteins and controls PIP2 ciliary abundance. EMBO J 2015; 34: 2537–2556.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hoffmeister H, Babinger K, Gürster S, Cedzich A, Meese C, Schadendorf K et al. Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. J Cell Biol 2011; 192: 631–645.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K et al. Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 2010; 464: 1048–1051.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bangs FK, Schrode N, Hadjantonakis AK, Anderson KV . Lineage specificity of primary cilia in the mouse embryo. Nat Cell Biol 2015; 17: 113–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Larkins CE, Aviles GD, East MP, Kahn RA, Caspary T . Arl13b regulates ciliogenesis and the dynamic localization of Shh signaling proteins. Mol Biol Cell 2011; 22: 4694–4703.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. He X, Zhang L, Chen Y, Remke M, Shih D, Lu F et al. The G protein α subunit G αs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nat Med 2014; 20: 1035–1042.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Yeh C, Li A, Chuang JZ, Saito M, Cáceres A, Sung CH . IGF-1 activates a cilium-localized noncanonical Gβγ signaling pathway that regulates cell-cycle progression. Dev Cell 2013; 26: 358–368.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kong AM, Horan KA, Sriratana A, Bailey CG, Collyer LJ, Nandurkar HH et al. Phosphatidylinositol 3-phosphate [PtdIns(3)P] is generated at the plasma membrane by an inositol polyphosphate 5-phosphatase: endogenous PtdIns(3)P can promote GLUT4 translocation to the plasma membrane. Mol Cell Biol 2006; 26: 6065–6081.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nielsen BS, Malinda RR, Schmid FM, Pedersen SF, Christensen ST, Pedersen LB . PDGFRβ and oncogenic mutant PDGFRα D842V promote disassembly of primary cilia through a PLCγ- and AURKA-dependent mechanism. J Cell Sci 2015; 128: 3543–3549.

    CAS  PubMed  Google Scholar 

  61. Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M et al. pVHL and PTEN tumor suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 2008; 27: 1747–1757.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Higginbotham H, Guo J, Yokota Y, Umberger NL, Su C-Y, Li J et al. Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation. Nat Neurosci 2013; 1: 1000–1007.

    Google Scholar 

  63. Zhu D, Shi S, Wang H, Liao K . Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J Cell Sci 2009; 122: 2760–2768.

    CAS  PubMed  Google Scholar 

  64. Thoma CR, Frew IJ, Hoerner CR, Montani M, Moch H, Krek W . pVHL and GSK3β are components of a primary cilium-maintenance signaling network. Nat Cell Biol 2007; 9: 588–595.

    CAS  PubMed  Google Scholar 

  65. Zhang B, Zhang T, Wang G, Wang G, Chi W, Jiang Q et al. GSK3β-Dzip1-Rab8 cascade regulates ciliogenesis after mitosis. PLoS Biol 2015; 13: e1002129.

    PubMed  PubMed Central  Google Scholar 

  66. Yip SC, El-Sibai M, Coniglio SJ, Mouneimne G, Eddy RJ, Drees BE et al. The distinct roles of Ras and Rac in PI 3-kinase-dependent protrusion during EGF-stimulated cell migration. J Cell Sci 2007; 120: 3138–3146.

    CAS  PubMed  Google Scholar 

  67. Yip SC, Eddy RJ, Branch AM, Pang H, Wu H, Yan Y et al. Quantification of PtdIns(3,4,5)P(3) dynamics in EGF-stimulated carcinoma cells: a comparison of PH-domain-mediated methods with immunological methods. Biochem J 2008; 411: 441–448.

    CAS  PubMed  Google Scholar 

  68. Hammond GR, Schiavo G, Irvine RF . Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P2 . Biochem J 2009; 422: 23–35.

    CAS  PubMed  Google Scholar 

  69. Franco I, Gulluni F, Campa CC, Costa C, Margaria JP, Ciraolo E et al. PI3K Class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Dev Cell 2014; 28: 647–658.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PRJ, Reese CB et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr Biol 1997; 7: 261–269.

    CAS  PubMed  Google Scholar 

  71. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 2005; 307: 1098–1101.

    CAS  PubMed  Google Scholar 

  72. Plotnikova OV, Seo S, Cottle DL, Conduit S, Hakim S, Dyson JM et al. INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. J Cell Sci 2015; 128: 364–372.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Eramo MJ, Mitchell CA . Regulation of PtdIns(3,4,5)P3/Akt signaling by inositol polyphosphate 5-phosphatases. Biochem Soc Trans 2016; 44: 240–252.

    CAS  PubMed  Google Scholar 

  74. Casamayor A, Morrice NA, Alessi DR . Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 1999; 342: 287–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL et al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget 2014; 5: 2881–2911.

    PubMed  PubMed Central  Google Scholar 

  76. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–789.

    CAS  PubMed  Google Scholar 

  77. Cho Y, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 2011; 29: 1424–1430.

    PubMed  Google Scholar 

  78. Northcott PA, Shih DJH, Peacock J, Garzia L, Morrissy AS, Zichner T et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012; 488: 49–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Remke M, Hielscher T, Korshunov A, Northcott PA, Bender S, Kool M et al. FSTL5 Is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. J Clin Oncol 2011; 29: 3852–3861.

    CAS  PubMed  Google Scholar 

  80. Wong SY, Seol AD, So PL, Ermilov AN, Bichakjian CK, Epstein EH et al. Primary cilia can both mediate and suppress hedgehog pathway-dependent tumorigenesis. Nat Med 2009; 15: 1055–1061.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Saeed H, Qiu W, Li C, Flyvbjerg A, Abdallah BM, Kassem M . Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway. Biogerontology 2015; 16: 733–745.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Elia D, Madhala D, Ardon E, Reshef R, Halevy O . Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: Involvement of MAPK/ERK and PI3K/Akt pathways. Biochim Biophys Acta 2007; 1773: 1438–1446.

    CAS  PubMed  Google Scholar 

  83. Riobó NA, Lu K, Ai X, Haines GM, Emerson CP . Phosphoinositide 3-kinase and Akt are essential for sonic hedgehog signaling. Proc Natl Acad Sci USA 2006; 103: 4505–4510.

    PubMed  PubMed Central  Google Scholar 

  84. Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA . HEF1-dependent aurora A activation induces disassembly of the primary cilium. Cell 2007; 129: 1351–1363.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Varnai P, Bondeva T, Tamas P, Toth B, Buday L, Hunyady L et al. Selective cellular effects of overexpressed pleckstrin-homology domains that recognize PtdIns(3,4,5)P3 suggest their interaction with protein binding partners. J Cell Sci 2005; 118: 4879–4888.

    CAS  PubMed  Google Scholar 

  86. Hsieh AC, Bo R, Manola J, Vazquez F, Bare O, Khvorova A et al. A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens. Nucleic Acids Res 2004; 32: 893–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci USA 1999; 96: 2110–2115.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D et al. A novel somatic mouse model to survey tumorigenic potential applied to the hedgehog pathway. Cancer Res 2006; 66: 10171–10178.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Matei V, Pauley S, Kaing S, Rowitch D, Beisel KW, Morris K et al. Smaller inner ear sensory epithelia in Neurog 1 null mice are related to earlier hair cell cycle exit. Dev Dyn 2005; 234: 633–650.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Dussault AA, Pouliot M . Rapid and simple comparison of messenger RNA levels using real-time PCR. Biol Proced Online 2006; 8: 1–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yee LE, Garcia-Gonzalo FR, Bowie RV, Li C, Kennedy JK, Ashrafi K et al. Conserved genetic interactions between ciliopathy complexes cooperatively support ciliogenesis and ciliary signaling. PLoS Genet 2015; 11: e1005627.

    PubMed  PubMed Central  Google Scholar 

  92. Ooms LM, Binge LC, Davies EM, Rahman P, Conway JRW, Gurung R et al. The inositol polyphosphate 5-phosphatase PIPP regulates AKT1-dependent breast cancer growth and metastasis. Cancer Cell 2015; 28: 155–169.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study utilized the Monash Micro Imaging Facility, Monash University, Victoria, Australia and Monash Histology Platform, Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia. This work was funded by a National Health and Medical Research Council project grant (APP1046174). SEC was supported by an Australian Postgraduate Award. VR is supported by a Young Investigator Award from Alex’s Lemonade Stand and a Basic Science Fellowship from the CERN foundation. MDT is supported by grants from the Pediatric Brain Tumor Foundation and the National Institutes of Health (R01CA159859 and R01CA148699).

Author contributions

SEC performed experiments. VR and MDT analysed human expression and copy number data. MR and MDT analysed human survival data. DNW and BJW provided advice and reagents. SEC, CAM and JMD formulated hypotheses, designed experiments and analysed data. The manuscript was written by SEC, CAM and JMD and edited by all authors.

Author information

Author notes

  1. C A Mitchell and J M Dyson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Cancer Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    S E Conduit, C A Mitchell & J M Dyson

  2. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

    V Ramaswamy

  3. The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada

    M Remke & M D Taylor

  4. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    D N Watkins

  5. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, New South Wales, Australia

    D N Watkins

  6. Department of Thoracic Medicine, St Vincent's Hospital, Darlinghurst, New South Wales, Australia

    D N Watkins

  7. Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    B J Wainwright

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  1. S E Conduit
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  2. V Ramaswamy
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  3. M Remke
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  4. D N Watkins
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  5. B J Wainwright
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  6. M D Taylor
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  7. C A Mitchell
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  8. J M Dyson
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Corresponding author

Correspondence to C A Mitchell.

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Supplementary Information accompanies this paper on the Oncogene website

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Conduit, S., Ramaswamy, V., Remke, M. et al. A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma. Oncogene 36, 5969–5984 (2017). https://doi.org/10.1038/onc.2017.208

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  • DOI: https://doi.org/10.1038/onc.2017.208

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