FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation


The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.

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Connective tissue growth factor


Negative control


Neuronal stem cell


Non-targeting sequence


Quantitative real time PCR


Retinoic acid


Transcriptional enhancer activator (TEA) domain




  1. 1.

    Sadeqzadeh E, de Bock CE, Thorne RF (2014) Sleeping giants: emerging roles for the fat cadherins in health and disease. Med Res Rev 34(1):190–221. doi:10.1002/med.21286

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Dunne J, Hanby AM, Poulsom R, Jones TA, Sheer D, Chin WG, Da SM, Zhao Q, Beverley PC, Owen MJ (1995) Molecular cloning and tissue expression of FAT, the human homologue of the Drosophila fat gene that is located on chromosome 4q34-q35 and encodes a putative adhesion molecule. Genomics 30(2):207–223 (pii: S0888754385798849)

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Matsui S, Utani A, Takahashi K, Mukoyama Y, Miyachi Y, Matsuyoshi N (2007) Human Fat2 is localized at immature adherens junctions in epidermal keratinocytes. J Dermatol Sci 48(3):233–236. doi:10.1016/j.jdermsci.2007.07.010

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Ciani L, Patel A, Allen ND, Ffrench-Constant C (2003) Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 23(10):3575–3582

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  5. 5.

    Saburi S, Hester I, Goodrich L, McNeill H (2012) Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity. Development 139(10):1806–1820. doi:10.1242/dev.077461

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  6. 6.

    Cox B, Hadjantonakis AK, Collins JE, Magee AI (2000) Cloning and expression throughout mouse development of mfat1, a homologue of the Drosophila tumour suppressor gene fat. Dev Dyn 217(3):233–240. doi:10.1002/(SICI)1097-0177(200003)217:3<233:AID-DVDY1>3.0.CO;2-O

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Ponassi M, Jacques TS, Ciani L, Ffrench Constant C (1999) Expression of the rat homologue of the Drosophila fat tumour suppressor gene. Mech Dev 80(2):207–212

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6(10):777–788. doi:10.1038/nrm1739

    Article  PubMed  Google Scholar 

  10. 10.

    Gincberg G, Arien-Zakay H, Lazarovici P, Lelkes PI (2012) Neural stem cells: therapeutic potential for neurodegenerative diseases. Br Med Bull 104:7–19. doi:10.1093/bmb/lds024

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2010) Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res 68(5):419–422. doi:10.1203/PDR.0b013e3181f1c289

    PubMed  Google Scholar 

  12. 12.

    Shoae-Hassani A, Mortazavi-Tabatabaei SA, Sharif S, Rezaei-Khaligh H, Verdi J (2011) DHEA provides a microenvironment for endometrial stem cells neurogenesis. Med Hypotheses 76(6):843–846. doi:10.1016/j.mehy.2011.02.033

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y (2004) The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 131(12):2791–2801. doi:10.1242/dev.01165

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Guo Y, Wang P, Sun H, Cai R, Xia W, Wang S (2013) Advanced glycation end product-induced astrocytic differentiation of cultured neurospheres through inhibition of Notch-Hes1 pathway-mediated neurogenesis. Int J Mol Sci 15(1):159–170. doi:10.3390/ijms15010159

    PubMed Central  Article  PubMed  Google Scholar 

  15. 15.

    Lin YT, Ding JY, Li MY, Yeh TS, Wang TW, Yu JY (2012) YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway. Exp Cell Res 318(15):1877–1888. doi:10.1016/j.yexcr.2012.05.005

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Cao X, Pfaff SL, Gage FH (2008) YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev 22(23):3320–3334. doi:10.1101/gad.1726608

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  17. 17.

    Zhang H, Deo M, Thompson RC, Uhler MD, Turner DL (2012) Negative regulation of Yap during neuronal differentiation. Dev Biol 361(1):103–115. doi:10.1016/j.ydbio.2011.10.017

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  18. 18.

    Zhao B, Li L, Lei Q, Guan KL (2010) The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 24(9):862–874. doi:10.1101/gad.1909210

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  19. 19.

    Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H (2009) The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16(3):398–410. doi:10.1016/j.devcel.2009.02.003

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Zhao B, Li L, Guan KL (2010) Hippo signaling at a glance. J Cell Sci 123(Pt 23):4001–4006. doi:10.1242/jcs.069070

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  21. 21.

    Beyer TA, Weiss A, Khomchuk Y, Huang K, Ogunjimi AA, Varelas X, Wrana JL (2013) Switch enhancers interpret TGF-beta and Hippo signaling to control cell fate in human embryonic stem cells. Cell Rep 5(6):1611–1624. doi:10.1016/j.celrep.2013.11.021

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Wrighton KH, Dai F, Feng XH (2008) A new kid on the TGFbeta block: tAZ controls Smad nucleocytoplasmic shuttling. Dev Cell 15(1):8–10. doi:10.1016/j.devcel.2008.06.010

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL (2008) TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10(7):837–848. doi:10.1038/ncb1748

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, Jafar-Nejad H, Halder G (2006) The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 8(1):27–36. doi:10.1038/ncb1339

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Kawamori H, Tai M, Sato M, Yasugi T, Tabata T (2011) Fat/Hippo pathway regulates the progress of neural differentiation signaling in the Drosophila optic lobe. Dev Growth Differ 53(5):653–667. doi:10.1111/j.1440-169X.2011.01279.x

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Van Hateren NJ, Das RM, Hautbergue GM, Borycki AG, Placzek M, Wilson SA (2011) FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools. Development 138(10):1893–1902. doi:10.1242/dev.064204

    PubMed Central  Article  PubMed  Google Scholar 

  27. 27.

    Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B, Engel C, Moeller MJ, Englert C, Bollig F, Schafer T, Ramachandran H, Mlodzik M, Huber TB, Kuehn EW, Kim E, Kramer-Zucker A, Walz G (2009) Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci USA 106(21):8579–8584. doi:10.1073/pnas.0811691106

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  28. 28.

    Liu H, Jiang D, Chi F, Zhao B (2012) The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation. Protein Cell 3(4):291–304. doi:10.1007/s13238-012-2919-3

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Hiemer SE, Varelas X (2013) Stem cell regulation by the Hippo pathway. Biochim Biophys Acta 1830 2:2323–2334. doi:10.1016/j.bbagen.2012.07.005

    Article  Google Scholar 

  30. 30.

    Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25(24):2594–2609. doi:10.1101/gad.176800.111

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  31. 31.

    Leli U, Cataldo A, Shea TB, Nixon RA, Hauser G (1992) Distinct mechanisms of differentiation of SH-SY5Y neuroblastoma cells by protein kinase C activators and inhibitors. J Neurochem 58(4):1191–1198

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Ota A, Shen-Orr Z, Roberts CT Jr, LeRoith D (1989) TPA-induced neurite formation in a neuroblastoma cell line (SH-SY5Y) is associated with increased IGF-I receptor mRNA and binding. Brain Res Mol Brain Res 6(1):69–76

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Peddada S, Yasui DH, LaSalle JM (2006) Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome. Hum Mol Genet 15(12):2003–2014. doi:10.1093/hmg/ddl124

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  34. 34.

    de Bock CE, Ardjmand A, Molloy TJ, Bone SM, Johnstone D, Campbell DM, Shipman KL, Yeadon TM, Holst J, Spanevello MD, Nelmes G, Catchpoole DR, Lincz LF, Boyd AW, Burns GF, Thorne RF (2012) The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis-relapse samples of precursor B-cell acute lymphoblastic leukemia. Leukemia 26(5):918–926. doi:10.1038/leu.2011.319

    Article  PubMed  Google Scholar 

  35. 35.

    Hartl D, Irmler M, Romer I, Mader MT, Mao L, Zabel C, de Angelis MH, Beckers J, Klose J (2008) Transcriptome and proteome analysis of early embryonic mouse brain development. Proteomics 8(6):1257–1265. doi:10.1002/pmic.200700724

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, Cord B, Palmer TD, Chikahisa S, Nishino S, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17(12):1657–1662. doi:10.1038/nm.2576

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  37. 37.

    Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M, Abhyankar A, Ying SW, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova JL, Studer L, Notarangelo LD (2012) Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491(7426):769–773. doi:10.1038/nature11583

    PubMed Central  CAS  PubMed  Google Scholar 

  38. 38.

    Sadeqzadeh E, de Bock CE, Zhang XD, Shipman KL, Scott NM, Song C, Yeadon T, Oliveira CS, Jin B, Hersey P, Boyd AW, Burns GF, Thorne RF (2011) Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products. J Biol Chem 286(32):28181–28191. doi:10.1074/jbc.M111.234419

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  39. 39.

    Berggren WT, Lutz M, Modesto V (2008) General spinfection protocol. In: Berggren WT, Lutz M, Modesto V (eds) StemBook: 2012. Cambridge

  40. 40.

    Sontag JM, Nunbhakdi-Craig V, Mitterhuber M, Ogris E, Sontag E (2010) Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. J Neurochem 115(6):1455–1465. doi:10.1111/j.1471-4159.2010.07049.x

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  41. 41.

    Dehmelt L, Smart FM, Ozer RS, Halpain S (2003) The role of microtubule-associated protein 2c in the reorganization of microtubules and lamellipodia during neurite initiation. J Neurosci 23(29):9479–9490

    CAS  PubMed  Google Scholar 

  42. 42.

    Michaelson D, Abidi W, Guardavaccaro D, Zhou M, Ahearn I, Pagano M, Philips MR (2008) Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division. J Cell Biol 181(3):485–496. doi:10.1083/jcb.200801047

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  43. 43.

    Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S (2008) A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2(6):525–528. doi:10.1016/j.stem.2008.05.011

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Perez-Polo JR, Werbach-Perez K, Tiffany-Castiglioni E (1979) A human clonal cell line model of differentiating neurons. Dev Biol 71(2):341–355

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Zhao B, Ye X, Yu J, Li L, Li W, Li S, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL (2008) TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22(14):1962–1971. doi:10.1101/gad.1664408

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  46. 46.

    Lai D, Ho KC, Hao Y, Yang X (2011) Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 71(7):2728–2738. doi:10.1158/0008-5472.CAN-10-2711

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Massague J, Wotton D (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 19(8):1745–1754. doi:10.1093/emboj/19.8.1745

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  48. 48.

    Zhang Y, Derynck R (1999) Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol 9(7):274–279

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Mao Y, Mulvaney J, Zakaria S, Yu T, Morgan KM, Allen S, Basson MA, Francis-West P, Irvine KD (2011) Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development 138(5):947–957. doi:10.1242/dev.057166

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  50. 50.

    Bossuyt W, Chen CL, Chen Q, Sudol M, McNeill H, Pan D, Kopp A, Halder G (2013) An evolutionary shift in the regulation of the Hippo pathway between mice and flies. Oncogene. doi:10.1038/onc.2013.82

    PubMed Central  PubMed  Google Scholar 

  51. 51.

    Castillejo-Lopez C, Arias WM, Baumgartner S (2004) The fat-like gene of Drosophila is the true orthologue of vertebrate fat cadherins and is involved in the formation of tubular organs. J Biol Chem 279(23):24034–24043. doi:10.1074/jbc.M313878200

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Cappello S, Gray MJ, Badouel C, Lange S, Einsiedler M, Srour M, Chitayat D, Hamdan FF, Jenkins ZA, Morgan T, Preitner N, Uster T, Thomas J, Shannon P, Morrison V, Di Donato N, Van Maldergem L, Neuhann T, Newbury-Ecob R, Swinkells M, Terhal P, Wilson LC, Zwijnenburg PJ, Sutherland-Smith AJ, Black MA, Markie D, Michaud JL, Simpson MA, Mansour S, McNeill H, Gotz M, Robertson SP (2013) Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat Genet 45(11):1300–1308. doi:10.1038/ng.2765

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Blair IP, Chetcuti AF, Badenhop RF, Scimone A, Moses MJ, Adams LJ, Craddock N, Green E, Kirov G, Owen MJ, Kwok JB, Donald JA, Mitchell PB, Schofield PR (2006) Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele. Mol Psychiatry 11(4):372–383. doi:10.1038/sj.mp.4001784

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485(7397):242–245. doi:10.1038/nature11011

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  55. 55.

    Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan S, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK, Chan TA (2013) Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 45(3):253–261. doi:10.1038/ng.2538

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  56. 56.

    Moeller MJ, Soofi A, Braun GS, Li X, Watzl C, Kriz W, Holzman LB (2004) Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization. EMBO J 23(19):3769–3779. doi:10.1038/sj.emboj.7600380

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  57. 57.

    Tanoue T, Takeichi M (2005) New insights into Fat cadherins. J Cell Sci 118(Pt 11):2347–2353. doi:10.1242/jcs.02398

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Dent EW, Kwiatkowski AV, Mebane LM, Philippar U, Barzik M, Rubinson DA, Gupton S, Van Veen JE, Furman C, Zhang J, Alberts AS, Mori S, Gertler FB (2007) Filopodia are required for cortical neurite initiation. Nat Cell Biol 9(12):1347–1359. doi:10.1038/ncb1654

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Kranz D, Boutros M (2014) A synthetic lethal screen identifies FAT1 as an antagonist of caspase-8 in extrinsic apoptosis. EMBO J 33(3):181–197. doi:10.1002/embj.201385686

    PubMed Central  CAS  PubMed  Google Scholar 

  60. 60.

    Lange C, Huttner WB, Calegari F (2009) Cdk4/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell 5(3):320–331. doi:10.1016/j.stem.2009.05.026

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Lobjois V, Bel-Vialar S, Trousse F, Pituello F (2008) Forcing neural progenitor cells to cycle is insufficient to alter cell-fate decision and timing of neuronal differentiation in the spinal cord. Neural Dev 3:4. doi:10.1186/1749-8104-3-4

    PubMed Central  Article  PubMed  Google Scholar 

  62. 62.

    Lobjois V, Benazeraf B, Bertrand N, Medevielle F, Pituello F (2004) Specific regulation of cyclins D1 and D2 by FGF and Shh signaling coordinates cell cycle progression, patterning, and differentiation during early steps of spinal cord development. Dev Biol 273(2):195–209. doi:10.1016/j.ydbio.2004.05.031

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Bennett FC, Harvey KF (2006) Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol 16(21):2101–2110. doi:10.1016/j.cub.2006.09.045

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    Silva E, Tsatskis Y, Gardano L, Tapon N, McNeill H (2006) The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway. Curr Biol 16(21):2081–2089. doi:10.1016/j.cub.2006.09.004

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE (2006) The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. J Cell Biol 173(3):417–429. doi:10.1083/jcb.200508121

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  66. 66.

    Hergovich A (2011) MOB control: reviewing a conserved family of kinase regulators. Cell Signal 23(9):1433–1440. doi:10.1016/j.cellsig.2011.04.007

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  67. 67.

    Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S (2013) A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154(5):1047–1059. doi:10.1016/j.cell.2013.07.042

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183. doi:10.1038/nature10137

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Hergovich A (2013) Regulation and functions of mammalian LATS/NDR kinases: looking beyond canonical Hippo signalling. Cell Biosci 3(1):32. doi:10.1186/2045-3701-3-32

    PubMed Central  Article  PubMed  Google Scholar 

  70. 70.

    Varelas X (2013) Non-canonical roles for the Hippo pathway. In: Oren M, Aylon Y (eds) The Hippo signaling pathway and cancer. Springer Science & Business Media, pp 327

  71. 71.

    Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL (2009) TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem 284(20):13355–13362. doi:10.1074/jbc.M900843200

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  72. 72.

    Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL (2005) High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307(5715):1621–1625. doi:10.1126/science.1105776

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Singh AM, Reynolds D, Cliff T, Ohtsuka S, Mattheyses AL, Sun Y, Menendez L, Kulik M, Dalton S (2012) Signaling network crosstalk in human pluripotent cells: a Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10(3):312–326. doi:10.1016/j.stem.2012.01.014

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  74. 74.

    Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26(1):54–68. doi:10.1101/gad.173435.111

    PubMed Central  Article  PubMed  Google Scholar 

  75. 75.

    Wada K, Itoga K, Okano T, Yonemura S, Sasaki H (2011) Hippo pathway regulation by cell morphology and stress fibers. Development 138(18):3907–3914. doi:10.1242/dev.070987

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Milgram SL (1999) Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. J Cell Biol 147(4):879–890

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  77. 77.

    Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB (2000) TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 19(24):6778–6791. doi:10.1093/emboj/19.24.6778

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  78. 78.

    Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147(4):759–772. doi:10.1016/j.cell.2011.09.048

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Rick F. Thorne.

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Ahmed, A.F., de Bock, C.E., Lincz, L.F. et al. FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation. Cell. Mol. Life Sci. 72, 4653–4669 (2015). https://doi.org/10.1007/s00018-015-1955-6

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  • FAT1 cadherin
  • Cadherin
  • Differentiation
  • Hippo pathway
  • Neurite outgrowth
  • Neuronal differentiation
  • SMAD transcription factor
  • TAZ
  • TGFβ signalling