Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth


Autoři: Ritu Sarpal aff001;  Victoria Yan aff001;  Lidia Kazakova aff001;  Luka Sheppard aff001;  Jessica C. Yu aff002;  Rodrigo Fernandez-Gonzalez aff001;  Ulrich Tepass aff001
Působiště autorů: Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada aff001;  Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada aff002;  Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada aff003
Vyšlo v časopise: Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008454
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008454

Souhrn

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling to AJs but also through a mechanism independent of Ajuba recruitment to AJs. Both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 causes Ajuba hyper-recruitment to AJs, promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

Klíčová slova:

Cell death – Cloning – Cytoskeleton – Drosophila melanogaster – Epithelium – Hyperexpression techniques – Lasers – c-Jun N-terminal kinase signaling cascade


Zdroje

1. Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat. Rev. Mol. Cell Biol. 2014; 15:397–410. doi: 10.1038/nrm3802 24824068

2. Takeichi M. Multiple functions of α-catenin beyond cell adhesion regulation. Curr Opin Cell Biol. 2018; 54:24–29. doi: 10.1016/j.ceb.2018.02.014 29525243

3. Pinheiro D, Bellaïche Y. Mechanical Force-Driven Adherens Junction Remodeling and Epithelial Dynamics. Dev Cell. 2018; 47:3–19. doi: 10.1016/j.devcel.2018.09.014 30300588

4. Charras G, Yap AS. Tensile Forces and Mechanotransduction at Cell-Cell Junctions. Curr Biol. 2018; 28: R445–R457. doi: 10.1016/j.cub.2018.02.003 29689229

5. Yap AS, Duszyc K, Viasnoff V. Mechanosensing and Mechanotransduction at Cell-Cell Junctions. Cold Spring Harb Perspect Biol. 2018; 10. pii: a028761. doi: 10.1101/cshperspect.a028761 28778874

6. Yonemura S, Wada Y, Watanabe T. Nagafuchi A, Shibata M. α-Catenin as a tension transducer that induces adherens junction development. Nat. Cell Biol. 2010; 12:533–542 doi: 10.1038/ncb2055 20453849

7. Buckley CD, Tan J, Anderson KL, Hanein D, Volkmann N, Weis WI, Nelson WJ, Dunn AR. 20 The minimal cadherin-catenin complex binds to actin filaments under force. Science 2014; 346: 1254211. doi: 10.1126/science.1254211 25359979

8. Ishiyama N, Tanaka N, Abe K, Yang YJ, Abbas YM, Umitsu M, Nagar B, Bueler SA, Rubinstein JL, Takeichi M, Ikura M. An autoinhibited structure of α-catenin and its implications for vinculin recruitment to adherens junctions. J. Biol. Chem. 2013; 288:15913–15925. doi: 10.1074/jbc.M113.453928 23589308

9. Ishiyama N, Sarpal R, Wood MN, Barrick SK, Nishikawal T, Hayashi H, Kobb AB, Flozak AS, Yemelyanov A, Fernaandez-Gonzalez R, Yonemura S, Leckband DE, Gottardi CJ, Tepass U, and Ikura M. Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions. Nat Commun. 2018; 9:5121. doi: 10.1038/s41467-018-07481-7 30504777

10. Rauskolb C, Shuguo S, Sun G, Pan Y, Irvine KD. Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell 2014; 158:143–156. doi: 10.1016/j.cell.2014.05.035 24995985

11. Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994; 1198:11–26. doi: 10.1016/0304-419x(94)90003-5 8199193

12. Benjamin JM, Nelson WJ. Bench to bedside and back again: molecular mechanisms of alpha-catenin function and roles in tumorigenesis. Semin Cancer Biol. 2008; 18:53–64. doi: 10.1016/j.semcancer.2007.08.003 17945508

13. Vasioukhin V. Adherens junctions and cancer. Subcell Biochem. 2012; 60:379–414. doi: 10.1007/978-94-007-4186-7_16 22674080

14. Karaman R, Halder G. Cell Junctions in Hippo Signaling. Cold Spring Harb Perspec Biol. 2018; 10. pii: a028753. doi: 10.1101/cshperspect.a028753 28600393

15. Misra JR, Irvine KD. The Hippo Signaling Network and Its Biological Functions. Annu Rev Genet. 2018; 52:65–87. doi: 10.1146/annurev-genet-120417-031621 30183404

16. Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V. α-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal. 2011; 4:ra33. doi: 10.1126/scisignal.2001823 21610251

17. Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell. 2011; 144:782–795. doi: 10.1016/j.cell.2011.02.031 21376238

18. Li P, Silvis MR, Honaker Y, Lien WH, Arron ST, Vasioukhin V. αE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway. Genes Dev. 2016; 30: 798–811. doi: 10.1101/gad.274951.115 27013234

19. Xu J, Vanderzalm PJ, Ludwig M, Su T, Tokamov SA Fehon RG. Yorkie Functions at the Cell Cortex to Promote Myosin Activation in a Non-transcriptional Manner. Dev Cell. 2018; 46:271–284. doi: 10.1016/j.devcel.2018.06.017 30032991

20. Das Thakur M, Feng Y, Jagannathan R, Seppa MJ, Longmore GD. Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr Biol. 2010; 20:657–662. doi: 10.1016/j.cub.2010.02.035 20303269

21. Pan Y, Heemskerk I, Ibar C, Shraiman BI, Irvine KD. Differential growth triggers mechanical feedback that elevates Hippo signaling. Proc Natl Acad Sci U S A. 2016; 113: E6974–E6983. doi: 10.1073/pnas.1615012113 27791172

22. Yang CC, Graves HK, Moya IM, Tao C, Hamaratoglu F, Gladden AB, Halder G. Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules. Proc Natl Acad Sci U S A. 2015; 112:1785–1790. doi: 10.1073/pnas.1420850112 25624491

23. le Duc Q, Shi Q, Blonk I, Sonnenberg A, Wang N, Leckband D, de Rooij J. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J Cell Biol. 2010; 189(7):1107–15. doi: 10.1083/jcb.201001149 20584916

24. Choi HJ, Pokutta S, Cadwell GW, Bobkov AA, Bankston LA, Liddington RC, Weis WI. αE-catenin is an autoinhibited molecule that coactivates vinculin. Proc Natl Acad Sci U S A. 2012; 109:8576–8581. doi: 10.1073/pnas.1203906109 22586082

25. Yao M, Qiu W, Liu R, Efremov AK, Cong P, Seddiki R, Payre M, Lim CT, Ladoux B, Mège RM, Yan J. Force-dependent conformational switch of α-catenin controls vinculin binding. Nat Commun. 2014; 5:4525. doi: 10.1038/ncomms5525 25077739

26. Hariharan IK. Organ Size Control: Lessons from Drosophila. Dev Cell. 2015; 34:255–265. doi: 10.1016/j.devcel.2015.07.012 26267393

27. Eder D, Aegerter C, Basler K. Forces controlling organ growth and size. Mech Dev. 2017; 144(Pt A):53–61. doi: 10.1016/j.mod.2016.11.005 27913118

28. Pan Y, Alégot H, Rauskolb C, Irvine KD. The dynamics of Hippo signaling during Drosophila wing development. Development 2018 Oct 17; 145(20). pii: dev165712. doi: 10.1242/dev.165712 30254143

29. Tepass U, Gruszynski-DeFeo E, Haag TA, Omatyar L, Török T, Hartenstein V. Shotgun encodes Drosophila E-cadherin and is preferentially required during cell rearrangement in the neurectoderm and other morphogenetically active epithelia. Genes Dev. 1996; 10:672–685. doi: 10.1101/gad.10.6.672 8598295

30. Sarpal R, Pellikka M, Patel RR, Hui FY, Godt D, Tepass U. Mutational analysis supports a core role for Drosophila α-catenin in adherens junction function. J. Cell Sci. 2012; 125:233–245. doi: 10.1242/jcs.096644 22266901

31. Kolahgar G, Bardet PL, Langton PF, Alexandre C, Vincent JP. Apical deficiency triggers JNK-dependent apoptosis in the embryonic epidermis of Drosophila. Development. 2011; 138:3021–3031. doi: 10.1242/dev.059980 21693518

32. Hay BA, Wolff T, Rubin GM. Expression of baculovirus P35 prevents cell death in Drosophila. Development. 1994; 120: 2121–2129. 7925015

33. Riesgo-Escovar JR, Jenni M, Fritz A, Hafen E. The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. Genes Dev. 1996; 10:2759–2768. doi: 10.1101/gad.10.21.2759 8946916

34. Martín-Blanco E, Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky AM, Martinez-Arias A. puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Genes Dev. 1998; 12(4):557–570. doi: 10.1101/gad.12.4.557 9472024

35. Short SP, Kondo J, Smalley-Freed WG, Takeda H, Dohn MR, Powell AE, Carnahan RH, Washington MK, Tripathi M, Payne DM, Jenkins NA, Copeland NG, Coffey RJ, Reynolds AB. P120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. J Clin Invest. 2017; 127:4462–4476. doi: 10.1172/JCI77217 29130932

36. Neisch AL, Speck O, Stronach B, Fehon RG. Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane. J Cell Biol. 2010; 189:311–323. doi: 10.1083/jcb.200912010 20404112

37. Khoo P, Allan K, Willoughby L, Brumby AM, Richardson HE. In Drosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1-Rok-Myosin-II and JNK signalling. Dis Model Mech. 2013; 6:661.678. doi: 10.1242/dmm.010066 23324326

38. Swarup S, Verheyen EM. 2012. Wnt/Wingless signaling in Drosophila. Cold Spring Harb Perspec Biol. 4:a007930. doi: 10.1101/csbperspec.a007930

39. Marie H, Pratt SJ, Betson M, Epple H, Kittler JT, Meek L, Moss SJ, Troyanovsky S, Attwell D, Longmore GD, Braga VM. The LIM protein Ajuba is recruited to cadherin-dependent cell junctions through an association with alpha-catenin. J. Biol. Chem. 2003; 278: 1220–1228. doi: 10.1074/jbc.M205391200 12417594

40. Alegot H, Markosian C, Rauskolb C, Yang J, Kirichenko E, Wang YC, Irvine KD. Recruitment of Jub by α-catenin promotes Yki activity and Drosophila wing growth. J Cell Sci. 2019; 132. pii:jcs222018. doi: 10.1242/jcs.222018 30659113

41. Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H. Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J Cell Sci. 1994; 107:3655–3663. 7706414

42. Pokutta S, Weis WI. Structure of the dimerization and beta-catenin-binding region of alpha-catenin. Mol Cell. 2000; 5:533–543. doi: 10.1016/s1097-2765(00)80447-5 10882138

43. Desai R, Sarpal R, Ishiyama N, Pellikka M, Ikura M, Tepass U. Monomeric α-catenin links cadherin to the actin cytoskeleton. Nat. Cell Biol. 2013; 15:261–273. doi: 10.1038/ncb2685 23417122

44. Sabino D, Brown NH, Basto R. Drosophila Ajuba is not an Aurora-A activator but is required to maintain Aurora-A at the centrosome. J Cell Sci. 2011; 124:1156–1166. doi: 10.1242/jcs.076711 21402878

45. Fulford A, Tapon N, Ribeiro PS. Upstairs, downstairs: spatial regulation of Hippo signalling. Curr Opin Cell Biol. 2018; 51:22–32. doi: 10.1016/j.ceb.2017.10.006 29154163

46. Diaz de la Loza MC, Thompson BJ. Forces shaping the Drosophila wing. Mech Dev. 2017; 144:23–32. doi: 10.1016/j.mod.2016.10.003 27784612

47. Mège R, Ishiyama N. Integration of Cadherin Adhesion and Cytoskeleton at Adherens Junctions. Cold Spring Harb Perspec Biol. 2017; 9:a028738. doi: 10.1101/cshperspect.a028738 28096263

48. Watabe-Uchida M, Uchida N, Imamura Y, Nagafuchi A, Fujimoto K, Uemura T, Vermeulen S, van Roy F, Adamson ED, Takeichi M. alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells. J Cell Biol. 1998;142(3):847–857. doi: 10.1083/jcb.142.3.847 9700171

49. Alatortsev VE, Kramerova IA, Frolov MV, Lavrov SA, Westphal ED. Vinculin gene is non-essential in Drosophila melanogaster. FEBS Lett. 1997; 413:197–201. doi: 10.1016/s0014-5793(97)00901-0 9280281

50. Klapholz B, Herbert SL, Wellman J, Johnson R, Parsons M, Brown NH. Alternative mechanisms for talin to mediate integrin function. Curr Biol. 2015; 25:847–857. doi: 10.1016/j.cub.2015.01.043 25754646

51. Razzell W, Bustillo ME, Zallen JA. The force-sensitive protein Ajuba regulates cell adhesion during epithelial morphogenesis. J Cell Biol. 2018; 217:3715–3730. doi: 10.1083/jcb.201801171 30006462

52. Zulueta-Coarasa T, Fernandez-Gonzalez R. Laser ablation to investigate cell and tissue mechanics in vivo. Integrative Mechanobiology: Micro-and Nano Techniques in Cell Mechanobiology, 2015; 110–127.

53. Fernandez-Gonzalez R, de Matos Simoes S, Röper JC, Eaton S, Zallen JA. Myosin II dynamics are regulated by tension in intercalating cells. Developmental cell 2009; 17(5), 736–743. doi: 10.1016/j.devcel.2009.09.003 19879198

54. Gumbiner BM, Kim NG. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci. 2014; 127:709–717. doi: 10.1242/jcs.140103 24532814

55. Enomoto M, Kizawa D, Ohsawa S, Igaki T. JNK signaling is converted form anti- to pro-tumor pathway by Ras-mediated switch of Warts activity. Dev Biol. 2015; 403:162–171. doi: 10.1016/j.ydbio.2015.05.001 25967126

56. Vite A, Li J, Radice GL. New functions for alpha-catenins in health and disease: from cancer to heart regeneration. Cell Tissue Res 2015; Jun, 360(3): 773–783. doi: 10.1007/s00441-015-2123-x 25673211

57. Shibata H, Takano H, Ito M, Shioya H, Hirota M, Matsumoto H, Kakudo Y, Ishioka C, Akiyama T, Kanegae Y, Saito I, Noda T. Alpha-catenin is essential in intestinal adenoma formation. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18199–204. doi: 10.1073/pnas.0705730104 17989230

58. Brumby AM, Goulding KR, Schlosser T, Loi S, Galea R, Khoo P, Bolden JE, Aigaki T, Humbert PO, Richardson HE. Identification of novel Ras-cooperating oncogenes in Drosophila melanogaster: a RhoGEF/Rho-family/JNK pathway is a central driver of tumorigenesis. Genetics 2011 May;188(1):105–25. doi: 10.1534/genetics.111.127910 21368274

59. Yue T, Tian A, Jiang J. The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Dev Cell. 2012; 22: 255–267. doi: 10.1016/j.devcel.2011.12.011 22280890

60. Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010; 20:582–590. doi: 10.1016/j.cub.2010.03.019 20362445

61. Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Pan D. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010; 107:10532–7. doi: 10.1073/pnas.1004279107 20498073

62. Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, Halder G. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 2010; 107:15810–15815. doi: 10.1073/pnas.1004060107 20798049

63. Drees F, Pokutta S, Yamanda S, Nelson WJ, Weis WI. Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 2005; 123:903–915. doi: 10.1016/j.cell.2005.09.021 16325583

64. Maître JL, Heisenberg CP. Three functions of cadherins in cell adhesion. Curr Biol. 2013; 23: R626–633. doi: 10.1016/j.cub.2013.06.019 23885883

65. Fernández BG, Gaspar P, Brás-Pereira C, Jezowska B, Rebelo SR and Janody F. Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 2011; 138:2337–2346. doi: 10.1242/dev.063545 21525075

66. Sansores-Garcia L, Bossuyt W, Wada K, Yonemura S, Tao C, Sasaki H, Halder G. Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 2011; 30:2325–2335. doi: 10.1038/emboj.2011.157 21556047

67. Sun Y, Zhang J, Ma L. α-catenin. A tumor suppressor beyond adherens junctions. Cell Cycle. 2014; 13:2334–9. doi: 10.4161/cc.29765 25483184

68. Sun S, Reddy BV, Irvine KD. Location of Hippo signalling complexes and Wart activation in vivo. Nat Commun. 2015; 6:8402. doi: 10.1038/ncomms9402 26420589

69. Ibar C, Kirichenko E, Keepers B, Enners E, Fleisch K, Irvine KD. Tension-dependent regulation of mammalian Hippo signaling through LIMD1. J Cell Sci. 2018; 131. pii: jcs214700. doi: 10.1242/jcs.214700 29440237

70. Kim TJ, Zheng S, Sun J, Muhamed I, Wu J, Lei L, Kong X, Leckband DE, Wang Y. Dynamic visualization of α-catenin reveals rapid, reversible conformation switching between tension states. Curr Biol. 2015; 25:218–224. doi: 10.1016/j.cub.2014.11.017 25544608

71. Barrick S, Li J, Kong X, Ray A, Tajkhorshid E, Leckband D. Salt bridges gate α-catenin activation at intercellular junctions. Mol Biol Cell. 2018; 29:111–122. doi: 10.1091/mbc.E17-03-0168 29142072

72. Kale GR, Yang X, Philippe JM, Mani M, Lenne PF, Lecuit T. Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis. Nat Commun. 2018; 9:5021. doi: 10.1038/s41467-018-07448-8 30479400

73. Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005; 122:421–434. doi: 10.1016/j.cell.2005.06.007 16096061

74. Oda H, Tsukita S. Dynamic features of adherens junctions during Drosophila embryonic epithelial morphogenesis revealed by a Alpha-catenin-GFP fusion protein. Dev Genes Evol. 1999; 209:218–225. doi: 10.1007/s004270050246 10079365

75. Groth AC, Fish M, Nusse R, Calos MP. Construction of transgenic Drosophila by using the site-specific integrase from phage phiC31. Genetics 2004; 166:1175–1782.

76. Vert JP, Foveau N, Lajaunie C, Vandenbrouck Y. An accurate and interpretable model for siRNA efficacy prediction. BMC Bioinformatics 2006; 7: 520. doi: 10.1186/1471-2105-7-520 17137497

77. Pellikka M, Tanentzapf G, Pinto M, Smith C, McGlade CJ, Ready DF, Tepass U. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 2002 Mar 14;416(6877):143–9. doi: 10.1038/nature721 11850625

78. Spratford CM, Kumar JP. Dissection and immunostaining of imaginal disks from Drosophila melanogaster. J Vis Exp. 2014; 91:51792. doi: 10.3791/51792 25285379

79. Fernandez-Gonzalez R, Zallen ZA. Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Phys. Biol. 2011; 8:045005. doi: 10.1088/1478-3975/8/4/045005 21750365

80. Leung CY, Fernandez-Gonzales R. Quantitative image analysis of cell behavior and molecular dynamics during tissue morphogenesis. Methods Mol. Biol. 2015; 1189:99–113. doi: 10.1007/978-1-4939-1164-6_7 25245689

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