A growing role for the Hippo signaling pathway in the heart

Abstract

Heart disease is a major cause of clinical morbidity and mortality, and a significant health and economic burden worldwide. The loss of functional cardiomyocytes, often a result of myocardial infarction, leads to impaired cardiac output and ultimately heart failure. Therefore, efforts to improve cardiomyocyte viability and stimulate cardiomyocyte proliferation remain attractive therapeutic goals. Originally identified in Drosophila, the Hippo signaling pathway is highly conserved from flies to humans and regulates organ size through modulation of both cell survival and proliferation. This is particularly relevant to the heart, an organ with limited regenerative ability. Recent work has demonstrated a critical role for this signaling cascade in determining heart development, homeostasis, injury and the potential for regeneration. Here we review the function of canonical and non-canonical Hippo signaling in cardiomyocytes, with a particular focus on proliferation and survival, and how this impacts the stressed adult heart.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Xu T, Wang W, Zhang S, Stewart RA, Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121:1053–1063

    CAS  PubMed  Google Scholar 

  2. 2.

    Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ (1995) The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev 9:534–546

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber DA, Hariharan IK (2002) Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110:467–478

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Wu S, Huang J, Dong J, Pan D (2003) Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114:445–456

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G (2003) Hippo promotes proliferation arrest and apoptosis in the salvador/warts pathway. Nat Cell Biol 5:914–920

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Pantalacci S, Tapon N, Leopold P (2003) The salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5:921–927

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Lai ZC, Wei X, Shimizu T, Ramos E, Rohrbaugh M, Nikolaidis N, Ho LL, Li Y (2005) Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120:675–685

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst ortholog, Hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457–467

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Huang J, Wu S, Barrera J, Matthews K, Pan D (2005) The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122:421–434

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D (2007) Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120–1133

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Yu FX, Zhao B, Guan KL (2015a) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163:811–828

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    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 154:1047–1059

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Sansores-Garcia L, Bossuyt W, Wada K, Yonemura S, Tao C, Sasaki H, Halder G (2011) Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J 30:2325–2335

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

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

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL (2011) Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25:51–63

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Paramasivam M, Sarkeshik A, Yates JR 3rd, Fernandes MJ, McCollum D (2011) Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol Biol Cell 22:3725–3733

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V (2011) Alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator YAP1. Sci Signal 4:ra33

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Li J, Gao E, Vite A, Yi R, Gomez L, Goossens S, van Roy F, Radice GL (2015) Alpha-catenins control cardiomyocyte proliferation by regulating YAP activity. Circ Res 116:70–79

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H et al (2012) Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150:780–791

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kim M, Kim M, Lee S, Kuninaka S, Saya H, Lee H, Lee S, Lim DS (2013) cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. EMBO J 32:1543–1555

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Mo JS, Yu FX, Gong R, Brown JH, Guan KL (2012) Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev 26:2138–2143

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Yu OM, Miyamoto S, Brown JH (2015b) Myocardin-related transcription factor a and yes-associated protein exert dual control in G protein-coupled receptor- and RhoA-mediated transcriptional regulation and cell proliferation. Mol Cell Biol 36:39–49

    PubMed  Google Scholar 

  24. 24.

    Shao D, Zhai P, Del Re DP, Sciarretta S, Yabuta N, Nojima H, Lim DS, Pan D, Sadoshima J (2014) A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun 5:3315

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Murakami M, Nakagawa M, Olson EN, Nakagawa O (2005) A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci U S A 102:18034–18039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, Zack TI, Wang X, Tsherniak A, Schinzel AC et al (2012) Beta-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 151:1457–1473

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y (1999) A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J 18:2551–2562

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA et al (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074–1078

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G (2001) Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 276:15164–15173

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A, Mauviel A (2002) Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21:4879–4884

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    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 10:837–848

    CAS  Article  PubMed  Google Scholar 

  32. 32.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA (2009b) YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11:1444–1450

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Lin Z, Zhou P, von Gise A, Gu F, Ma Q, Chen J, Guo H, van Gorp PR, Wang DZ, Pu WT (2015) Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res 116:35–45

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Tao G, Kahr PC, Morikawa Y, Zhang M, Rahmani M, Heallen TR, Li L, Sun Z, Olson EN, Amendt BA et al (2016) Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534:119–123

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Morikawa Y, Zhang M, Heallen T, Leach J, Tao G, Xiao Y, Bai Y, Li W, Willerson JT, Martin JF (2015) Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci Signal 8:ra41

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kim M, Kim T, Johnson RL, Lim DS (2015) Transcriptional co-repressor function of the Hippo pathway transducers YAP and TAZ. Cell Rep 11:270–282

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493:433–436

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, Ma Q, Ishiwata T, Zhou B, Camargo FD et al (2012) YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A 109:2394–2399

    Article  Google Scholar 

  42. 42.

    Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF (2011) Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332:458–461

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA, Bassel-Duby R, Olson EN (2011) Regulation of insulin-like growth factor signaling by YAP governs cardiomyocyte proliferation and embryonic heart size. Sci Signal 4:ra70

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lin Z, Guo H, Cao Y, Zohrabian S, Zhou P, Ma Q, VanDusen N, Guo Y, Zhang J, Stevens SM et al (2016) Acetylation of VGLL4 regulates Hippo-YAP signaling and postnatal cardiac growth. Dev Cell 39:466–479

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Houser SR, Margulies KB, Murphy AM, Spinale FG, Francis GS, Prabhu SD, Rockman HA, Kass DA, Molkentin JD, Sussman MA et al (2012) Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res 111:131–150

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, Sciarretta S, Del Re DP, Zablocki DK, Hsu CP et al (2013) Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 19:1478–1488

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Del Re DP, Matsuda T, Zhai P, Maejima Y, Jain MR, Liu T, Li H, Hsu CP, Sadoshima J (2014) Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell 54:639–650

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Chen SN, Gurha P, Lombardi R, Ruggiero A, Willerson JT, Marian AJ (2014) The Hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ Res 114:454–468

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Wackerhage H, Del Re DP, Judson RN, Sudol M, Sadoshima J (2014) The Hippo signal transduction network in skeletal and cardiac muscle. Sci Signal 7:re4

    Article  PubMed  Google Scholar 

  50. 50.

    Matsui Y, Nakano N, Shao D, Gao S, Luo W, Hong C, Zhai P, Holle E, Yu X, Yabuta N et al (2008) Lats2 is a negative regulator of myocyte size in the heart. Circ Res 103:1309–1318

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Avruch J, Xavier R, Bardeesy N, Zhang XF, Praskova M, Zhou D, Xia F (2009) Rassf family of tumor suppressor polypeptides. J Biol Chem 284:11001–11005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Del Re DP, Matsuda T, Zhai P, Gao S, Clark GJ, Van Der Weyden L, Sadoshima J (2010) Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. J Clin Invest 120:3555–3567

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Oceandy D, Pickard A, Prehar S, Zi M, Mohamed TM, Stanley PJ, Baudoin-Stanley F, Nadif R, Tommasi S, Pfeifer GP et al (2009) Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy. Circulation 120:607–616

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Zi M, Maqsood A, Prehar S, Mohamed TM, Abou-Leisa R, Robertson A, Cartwright EJ, Ray SG, Oh S, Lim DS et al (2014) The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy. J Biol Chem 289:24275–24288

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP et al (2016) Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 133:e38–360

    Article  Google Scholar 

  56. 56.

    Laflamme MA, Murry CE (2005) Regenerating the heart. Nat Biotechnol 23:845–856

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Hausenloy DJ, Yellon DM (2013) Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 123:92–100

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Yamamoto S, Yang G, Zablocki D, Liu J, Hong C, Kim SJ, Soler S, Odashima M, Thaisz J, Yehia G et al (2003) Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J Clin Invest 111:1463–1474

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Odashima M, Usui S, Takagi H, Hong C, Liu J, Yokota M, Sadoshima J (2007) Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res 100:1344–1352

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Zhang N, Bai H, David KK, Dong J, Zheng Y, Cai J, Giovannini M, Liu P, Anders RA, Pan D (2010) The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 19:27–38

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lavado A, He Y, Pare J, Neale G, Olson EN, Giovannini M, Cao X (2013) Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting YAP/Taz transcriptional coactivators. Development 140:3323–3334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Matsuda T, Zhai P, Sciarretta S, Zhang Y, Jeong JI, Ikeda S, Park J, Hsu CP, Tian B, Pan D et al (2016) NF2 activates Hippo signaling and promotes ischemia/reperfusion injury in the heart. Circ Res 119:596–606

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Nakamura M, Zhai P, Del Re DP, Maejima Y, Sadoshima J (2016) Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. JCI Insight 1

  64. 64.

    Del Re DP, Yang Y, Nakano N, Cho J, Zhai P, Yamamoto T, Zhang N, Yabuta N, Nojima H, Pan D et al (2013) Yes-associated protein isoform 1 (YAP1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J Biol Chem 288:3977–3988

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER, Mahmoud AI, Tan W, Shelton JM et al (2013) Hippo pathway effector YAP promotes cardiac regeneration. Proc Natl Acad Sci U S A 110:13839–13844

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Lin Z, von Gise A, Zhou P, Gu F, Ma Q, Jiang J, Yau AL, Buck JN, Gouin KA, van Gorp PR et al (2014) Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine myocardial infarction model. Circ Res 115:354–363

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Yang Y, Del Re DP, Nakano N, Sciarretta S, Zhai P, Park J, Sayed D, Shirakabe A, Matsushima S, Park Y et al (2015) miR-206 mediates YAP-induced cardiac hypertrophy and survival. Circ Res 117:891–904

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, Bresolin S, Frasson C, Basso G, Guzzardo V et al (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158:157–170

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, Martin JF (2013) Hippo signaling impedes adult heart regeneration. Development 140:4683–4690

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH R01HL127339 (D.P.D.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dominic P. Del Re.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Del Re, D.P. A growing role for the Hippo signaling pathway in the heart. J Mol Med 95, 465–472 (2017). https://doi.org/10.1007/s00109-017-1525-5

Download citation

Keywords

  • Cardiomyocyte
  • Heart disease
  • Hippo pathway