The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Huan Liu, Dandan Jiang, Fangtao Chi, Bin Zhao()

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Protein Cell ›› 2012, Vol. 3 ›› Issue (4) : 291-304. DOI: 10.1007/s13238-012-2919-3
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REVIEW

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

  • Huan Liu, Dandan Jiang, Fangtao Chi, Bin Zhao()
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Abstract

Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs. They play key roles during development and their dysregulation gives rise to human diseases such as cancer. The recent development of induced pluripotent stem cell (iPSC) technology which converts somatic cells to stem-like cells holds great promise for regenerative medicine. Nevertheless, the understanding of proliferation, differentiation, and self-renewal of stem cells and organ-specific progenitor cells is far from clear. Recently, the Hippo pathway was demonstrated to play important roles in these processes. The Hippo pathway is a newly established signaling pathway with critical functions in limiting organ size and suppressing tumorigenesis. This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

Keywords

Hippo pathway / stem cell / YAP / Lats / differentiation / self-renewal

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Huan Liu, Dandan Jiang, Fangtao Chi, Bin Zhao. The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation. Prot Cell, 2012, 3(4): 291‒304 https://doi.org/10.1007/s13238-012-2919-3

References

[1] Alarcón, C., Zaromytidou, A.I., Xi, Q., Gao, S., Yu, J., Fujisawa, S., Barlas, A., Miller, A.N., Manova-Todorova, K., Macias, M.J., . (2009). Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139, 757-769 .10.1016/j.cell.2009.09.035
[2] Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E., and Stocker, H. (2010). The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 18, 309-316 .10.1016/j.devcel.2009.12.013
[3] Benhamouche, S., Curto, M., Saotome, I., Gladden, A.B., Liu, C.H., Giovannini, M., and McClatchey, A.I. (2010). Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24, 1718-1730 .10.1101/gad.1938710
[4] Bennett, F.C., and Harvey, K.F. (2006). Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol 16, 2101-2110 .10.1016/j.cub.2006.09.045
[5] Bhat, K.P., Salazar, K.L., Balasubramaniyan, V., Wani, K., Heathcock, L., Hollingsworth, F., James, J.D., Gumin, J., Diefes, K.L., Kim, S.H., . (2011). The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25, 2594-2609 .10.1101/gad.176800.111
[6] Boggiano, J.C., Vanderzalm, P.J., and Fehon, R.G. (2011). Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev Cell 21, 888-895 .10.1016/j.devcel.2011.08.028
[7] Callus, B.A., Verhagen, A.M., and Vaux, D.L. (2006). Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J 273, 4264-4276 .10.1111/j.1742-4658.2006.05427.x
[8] Camargo, F.D., Gokhale, S., Johnnidis, J.B., Fu, D., Bell, G.W., Jaenisch, R., and Brummelkamp, T.R. (2007). YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17, 2054-2060 .10.1016/j.cub.2007.10.039
[9] Cao, X., Pfaff, S.L., and Gage, F.H. (2008). YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev 22, 3320-3334 .10.1101/gad.1726608
[10] Chan, E.H., Nousiainen, M., Chalamalasetty, R.B., Sch?fer, A., Nigg, E.A., and Silljé, H.H. (2005). The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076-2086 .10.1038/sj.onc.1208445
[11] Chan, S.W., Lim, C.J., Chong, Y.F., Venkatesan Pobbati, A., Huang, C., and Hong, W. (2011). Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem 286, 7018-7026 .10.1074/jbc.C110.212621
[12] Chan, S.W., Lim, C.J., Guo, K., Ng, C.P., Lee, I., Hunziker, W., Zeng, Q., and Hong, W. (2008). A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res 68, 2592-2598 .10.1158/0008-5472.CAN-07-2696
[13] Chen, C.L., Gajewski, K.M., Hamaratoglu, F., Bossuyt, W., Sansores-Garcia, L., Tao, C., and Halder, G. (2010a). The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A 107, 15810-15815 .10.1073/pnas.1004060107
[14] Chen, L., Chan, S.W., Zhang, X., Walsh, M., Lim, C.J., Hong, W., and Song, H. (2010b). Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes Dev 24, 290-300 .10.1101/gad.1865310
[15] Chen, L.F., Qin, F.N., Deng, X.M., Avruch, J., Zhou, D.W. (2012). Hippo pathway in intestinal homeostasis and tumorigenesis. Protein Cell 2012 April . doi: 10.1007/s13238-012-2913-9.10.1007/s13238-012-2913-910.1007/s13238-012-2913-9
[16] Chia, N.Y., Chan, Y.S., Feng, B., Lu, X., Orlov, Y.L., Moreau, D., Kumar, P., Yang, L., Jiang, J., Lau, M.S., . (2010). A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 468, 316-320 .10.1038/nature09531
[17] Cho, E., Feng, Y., Rauskolb, C., Maitra, S., Fehon, R., and Irvine, K.D. (2006). Delineation of a Fat tumor suppressor pathway. Nat Genet 38, 1142-1150 .10.1038/ng1887
[18] Cho, W.J., Shin, J.M., Kim, J.S., Lee, M.R., Hong, K.S., Lee, J.H., Koo, K.H., Park, J.W., and Kim, K.S. (2009). miR-372 regulates cell cycle and apoptosis of ags human gastric cancer cell line through direct regulation of LATS2. Mol Cells 28, 521-527 .10.1007/s10059-009-0158-0
[19] Chow, A., Hao, Y., and Yang, X. (2010). Molecular characterization of human homologs of yeast MOB1. Int J Cancer 126, 2079-2089 .
[20] Cordenonsi, M., Zanconato, F., Azzolin, L., Forcato, M., Rosato, A., Frasson, C., Inui, M., Montagner, M., Parenti, A.R., Poletti, A., . (2011). The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759-772 .10.1016/j.cell.2011.09.048
[21] Das Thakur, M., Feng, Y., Jagannathan, R., Seppa, M.J., Skeath, J.B., and Longmore, G.D. (2010). Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr Biol 20, 657-662 .10.1016/j.cub.2010.02.035
[22] Densham, R.M., O’Neill, E., Munro, J., K?nig, I., Anderson, K., Kolch, W., and Olson, M.F. (2009). MST kinases monitor actin cytoskeletal integrity and signal via c-Jun N-terminal kinase stress-activated kinase to regulate p21Waf1/Cip1 stability. Mol Cell Biol 29, 6380-6390 .10.1128/MCB.00116-09
[23] Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S.A., Gayyed, M.F., Anders, R.A., Maitra, A., and Pan, D. (2007). Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120-1133 .10.1016/j.cell.2007.07.019
[24] Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., . (2011). Role of YAP/TAZ in mechanotransduction. Nature 474, 179-183 .10.1038/nature10137
[25] Engler, A.J., Sen, S., Sweeney, H.L., and Discher, D.E. (2006). Matrix elasticity directs stem cell lineage specification. Cell 126, 677-689 .10.1016/j.cell.2006.06.044
[26] Feng, Y., and Irvine, K.D. (2009). Processing and phosphorylation of the Fat receptor. Proc Natl Acad Sci U S A 106, 11989-11994 .10.1073/pnas.0811540106
[27] Fernández, B.G., Gaspar, P., Brás-Pereira, C., Jezowska, B., Rebelo, S.R., and Janody, F. (2011). Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138, 2337-2346 .10.1242/dev.063545
[28] Fernandez-L, A., Northcott, P.A., Dalton, J., Fraga, C., Ellison, D., Angers, S., Taylor, M.D., and Kenney, A.M. (2009). YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 23, 2729-2741 .10.1101/gad.1824509
[29] Fossdal, R., Jonasson, F., Kristjansdottir, G.T., Kong, A., Stefansson, H., Gosh, S., Gulcher, J.R., and Stefansson, K. (2004). A novel TEAD1 mutation is the causative allele in Sveinsson’s chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration). Hum Mol Genet 13, 975-981 .10.1093/hmg/ddh106
[30] Gee, S.T., Milgram, S.L., Kramer, K.L., Conlon, F.L., and Moody, S.A. (2011). Yes-associated protein 65 (YAP) expands neural progenitors and regulates Pax3 expression in the neural plate border zone. PLoS One 6, e20309.10.1371/journal.pone.0020309
[31] Genevet, A., Polesello, C., Blight, K., Robertson, F., Collinson, L.M., Pichaud, F., and Tapon, N. (2009). The Hippo pathway regulates apical-domain size independently of its growth-control function. J Cell Sci 122, 2360-2370 .10.1242/jcs.041806
[32] Genevet, A., Wehr, M.C., Brain, R., Thompson, B.J., and Tapon, N. (2010). Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 18, 300-308 .10.1016/j.devcel.2009.12.011
[33] Goulev, Y., Fauny, J.D., Gonzalez-Marti, B., Flagiello, D., Silber, J., and Zider, A. (2008). SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr Biol 18, 435-441 .10.1016/j.cub.2008.02.034
[34] Graves, J.D., Gotoh, Y., Draves, K.E., Ambrose, D., Han, D.K., Wright, M., Chernoff, J., Clark, E.A., and Krebs, E.G. (1998). Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 17, 2224-2234 .10.1093/emboj/17.8.2224
[35] Grzeschik, N.A., Parsons, L.M., Allott, M.L., Harvey, K.F., and Richardson, H.E. (2010). Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20, 573-581 .10.1016/j.cub.2010.01.055
[36] Guo, C., Tommasi, S., Liu, L., Yee, J.K., Dammann, R., and Pfeifer, G.P. (2007). RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network. Curr Biol 17, 700-705 .10.1016/j.cub.2007.02.055
[37] Hall, C.A., Wang, R., Miao, J., Oliva, E., Shen, X., Wheeler, T., Hilsenbeck, S.G., Orsulic, S., and Goode, S. (2010). Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res 70, 8517-8525 .10.1158/0008-5472.CAN-10-1242
[38] Hamaratoglu, F., Willecke, M., Kango-Singh, M., Nolo, R., Hyun, E., Tao, C., Jafar-Nejad, H., and 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, 27-36 .10.1038/ncb1339
[39] Hao, Y., Chun, A., Cheung, K., Rashidi, B., and Yang, X. (2008). Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 283, 5496-5509 .10.1074/jbc.M709037200
[40] Hariharan, I.K., and Bilder, D. (2006). Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev Genet 40, 335-361 .10.1146/annurev.genet.39.073003.100738
[41] Harvey, K.F., Pfleger, C.M., and Hariharan, I.K. (2003). The DrosophilaMst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457-467 .10.1016/S0092-8674(03)00557-9
[42] Heallen, T., Zhang, M., Wang, J., Bonilla-Claudio, M., Klysik, E., Johnson, R.L., and Martin, J.F. (2011). Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458-461 .10.1126/science.1199010
[43] Hirabayashi, S., Nakagawa, K., Sumita, K., Hidaka, S., Kawai, T., Ikeda, M., Kawata, A., Ohno, K., and Hata, Y. (2008). Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene 27, 4281-4292 .10.1038/onc.2008.66
[44] Hisaoka, M., Tanaka, A., and Hashimoto, H. (2002). Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest 82, 1427-1435 .
[45] Hong, J.H., Hwang, E.S., McManus, M.T., Amsterdam, A., Tian, Y., Kalmukova, R., Mueller, E., Benjamin, T., Spiegelman, B.M., Sharp, P.A., . (2005). TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074-1078 .10.1126/science.1110955
[46] Huang, J., Wu, S., Barrera, J., Matthews, K., and 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 .10.1016/j.cell.2005.06.007
[47] Jansson, L., and Larsson, J. (2012). Normal Hematopoietic Stem Cell Function in Mice with Enforced Expression of the Hippo Signaling Effector YAP1. PLoS One 7, e32013.10.1371/journal.pone.0032013
[48] Jia, J., Zhang, W., Wang, B., Trinko, R., and Jiang, J. (2003). The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev 17, 2514-2519 .10.1101/gad.1134003
[49] Jiang, Z., Li, X., Hu, J., Zhou, W., Jiang, Y., Li, G., and Lu, D. (2006). Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56, 450-458 .10.1016/j.neures.2006.09.006
[50] Jiménez-Velasco, A., Román-Gómez, J., Agirre, X., Barrios, M., Navarro, G., Vázquez, I., Prósper, F., Torres, A., and Heiniger, A. (2005). Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19, 2347-2350 .10.1038/sj.leu.2403974
[51] Jin, Y., Dong, L., Lu, Y., Wu, W., Hao, Q., Zhou, Z., Jiang, J., Zhao, Y., and Zhang, L. (2012). Dimerization and cytoplasmic localization regulate hippo kinase signaling activity in organ size control. J Biol Chem 287, 5784-5796 .10.1074/jbc.M111.310334
[52] Justice, R.W., Zilian, O., Woods, D.F., Noll, M., and Bryant, P.J. (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 .10.1101/gad.9.5.534
[53] Kango-Singh, M., Nolo, R., Tao, C., Verstreken, P., Hiesinger, P.R., Bellen, H.J., and Halder, G. (2002). Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719-5730 .10.1242/dev.00168
[54] Karpowicz, P., Perez, J., and Perrimon, N. (2010). The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135-4145 .10.1242/dev.060483
[55] Kawamori, H., Tai, M., Sato, M., Yasugi, T., and Tabata, T. (2011). Fat/Hippo pathway regulates the progress of neural differentiation signaling in the Drosophila optic lobe. Dev Growth Differ 53, 653-667 .10.1111/j.1440-169X.2011.01279.x
[56] Khokhlatchev, A., Rabizadeh, S., Xavier, R., Nedwidek, M., Chen, T., Zhang, X.F., Seed, B., and Avruch, J. (2002). Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol 12, 253-265 .10.1016/S0960-9822(02)00683-8
[57] Kitagawa, M. (2007). A Sveinsson’s chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ. Biochem Biophys Res Commun 361, 1022-1026 .10.1016/j.bbrc.2007.07.129
[58] Lai, Z.C., Wei, X., Shimizu, T., Ramos, E., Rohrbaugh, M., Nikolaidis, N., Ho, L.L., and Li, Y. (2005). Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675-685 .10.1016/j.cell.2004.12.036
[59] Lee, J.H., Kim, T.S., Yang, T.H., Koo, B.K., Oh, S.P., Lee, K.P., Oh, H.J., Lee, S.H., Kong, Y.Y., Kim, J.M., . (2008). A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J 27, 1231-1242 .10.1038/emboj.2008.63
[60] Lee, K.P., Lee, J.H., Kim, T.S., Kim, T.H., Park, H.D., Byun, J.S., Kim, M.C., Jeong, W.I., Calvisi, D.F., Kim, J.M., . (2010). The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc Natl Acad Sci U S A 107, 8248-8253 .10.1073/pnas.0912203107
[61] Lei, Q.Y., Zhang, H., Zhao, B., Zha, Z.Y., Bai, F., Pei, X.H., Zhao, S., Xiong, Y., and Guan, K.L. (2008). TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28, 2426-2436 .10.1128/MCB.01874-07
[62] Li, Y., Hibbs, M.A., Gard, A.L., Shylo, N.A., and Yun, K. (2012). Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals di-rect transcriptional regulation of Wnt, SHH, and Hippo pathway effectors by Notch1. Stem Cells 2012Jan9. doi: 10.1002/stem.1030. [Epub ahead of print]10.1002/stem.103010.1002/stem.1030
[63] Li, Z., Zhao, B., Wang, P., Chen, F., Dong, Z., Yang, H., Guan, K.L., and Xu, Y. (2010). Structural insights into the YAP and TEAD complex. Genes Dev 24, 235-240 .10.1101/gad.1865810
[64] Lian, I., Kim, J., Okazawa, H.,Zhao, J., Zhao, B., Yu, J., Chinnaiyan, A., Israel, M.A., Goldstein, L.S., Abujarour, R., . (2010). The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24, 1106-1118 .10.1101/gad.1903310
[65] Ling, C., Zheng, Y., Yin, F., Yu, J., Huang, J., Hong, Y., Wu, S., and Pan, D. (2010). 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 107, 10532-10537 .10.1073/pnas.1004279107
[66] Liu, C.Y., Zha, Z.Y., Zhou, X., Zhang, H., Huang, W., Zhao, D., Li, T., Chan, S.W., Lim, C.J., Hong, W., . (2010). The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFbeta-TrCP E3 ligase. J Biol Chem 285, 37159-37169 .10.1074/jbc.M110.152942
[67] Lu, L., Li, Y., Kim, S.M., Bossuyt, W., Liu, P., Qiu, Q., Wang, Y., Halder, G., Finegold, M.J., Lee, J.S., . (2010). Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci U S A 107, 1437-1442 .10.1073/pnas.0911427107
[68] Mani, S.A., Guo, W., Liao, M.J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F., Zhang, C.C., Shipitsin, M., . (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 .10.1016/j.cell.2008.03.027
[69] Mao, Y., Kucuk, B., and Irvine, K.D. (2009). Drosophila lowfat, a novel modulator of Fat signaling. Development 136, 3223-3233 .10.1242/dev.036152
[70] Matakatsu, H., and Blair, S.S. (2006). Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315-2324 .10.1242/dev.02401
[71] Minoo, P., Zlobec, I., Baker, K., Tornillo, L., Terracciano, L., Jass, J.R., and Lugli, A. (2007). Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod Pathol 20, 331-338 .10.1038/modpathol.3800740
[72] Murakami, H., Mizuno, T., Taniguchi, T., Fujii, M., Ishiguro, F., Fukui, T., Akatsuka, S., Horio, Y., Hida, T., Kondo, Y., . (2011). LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res 71, 873-883 .10.1158/0008-5472.CAN-10-2164
[73] Neto-Silva, R.M., de Beco, S., and Johnston, L.A. (2010). Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev Cell 19, 507-520 .10.1016/j.devcel.2010.09.009
[74] Nishioka, N., Inoue, K., Adachi, K., Kiyonari, H., Ota, M., Ralston, A., Yabuta, N., Hirahara, S., Stephenson, R.O., Ogonuki, N., . (2009). The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16, 398-410 .10.1016/j.devcel.2009.02.003
[75] Nishioka, N., Yamamoto, S., Kiyonari, H., Sato, H., Sawada, A., Ota, M., Nakao, K., and Sasaki, H. (2008). Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev 125, 270-283 .10.1016/j.mod.2007.11.002
[76] Oh, H., and Irvine, K.D. (2008). In vivo regulation of Yorkie phosphorylation and localization. Development 135, 1081-1088 .10.1242/dev.015255
[77] Oh, H.J., Lee, K.K., Song, S.J., Jin, M.S., Song, M.S., Lee, J.H., Im, C.R., Lee, J.O., Yonehara, S., and Lim, D.S. (2006). Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res 66, 2562-2569 .10.1158/0008-5472.CAN-05-2951
[78] Oka, T., Mazack, V., and Sudol, M. (2008). Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J Biol Chem 283, 27534-27546 .10.1074/jbc.M804380200
[79] Oka, T., Remue, E., Meerschaert, K., Vanloo, B., Boucherie, C., Gfeller, D., Bader, G.D., Sidhu, S.S., Vandekerckhove, J., Gettemans, J., . (2010). Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling. Biochem J 432, 461-472 .10.1042/BJ20100870
[80] Overholtzer, M., Zhang, J., Smolen, G.A., Muir, B., Li, W., Sgroi, D.C., Deng, C.X., Brugge, J.S., and Haber, D.A. (2006). Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 103, 12405-12410 .10.1073/pnas.0605579103
[81] Pan, D. (2010). The hippo signaling pathway in development and cancer. Dev Cell 19, 491-505 .10.1016/j.devcel.2010.09.011
[82] Pantalacci, S., Tapon, N., and Léopold, P. (2003). The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5, 921-927 .10.1038/ncb1051
[83] Poernbacher, I., Baumgartner, R., Marada, S.K., Edwards, K., and Stocker, H. (2012). Drosophila pez acts in hippo signaling to restrict intestinal stem cell proliferation. Curr Biol 22, 389-396 .10.1016/j.cub.2012.01.019
[84] Poon, C.L., Lin, J.I., Zhang, X., and Harvey, K.F. (2011). The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev Cell 21, 896-906 .10.1016/j.devcel.2011.09.012
[85] Praskova, M., Khoklatchev, A., Ortiz-Vega, S., and Avruch, J. (2004). Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J 381, 453-462 .10.1042/BJ20040025
[86] Praskova, M., Xia, F., and Avruch, J. (2008). MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 18, 311-321 .10.1016/j.cub.2008.02.006
[87] Qin, H., Blaschke, K., Wei, G., Ohi, Y., Blouin, L., Qi, Z., Yu, J., Yeh, R.F., Hebrok, M., and Ramalho-Santos, M. (2012). Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming. Human Mol Genet Jan 27, 2012. doi: 10.1093/hmg/dds023. [published online]10.1093/hmg/dds02310.1093/hmg/dds023
[88] Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R.C., and Melton, D.A. (2002). “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298, 597-600 .10.1126/science.1072530
[89] Rauskolb, C., Pan, G., Reddy, B.V., Oh, H., and Irvine, K.D. (2011). Zyxin links fat signaling to the hippo pathway. PLoS Biol 9, e1000624.10.1371/journal.pbio.1000624
[90] Remue, E., Meerschaert, K., Oka, T., Boucherie, C., Vandekerckhove, J., Sudol, M., and Gettemans, J. (2010). TAZ interacts with zonula occludens-1 and-2 proteins in a PDZ-1 dependent manner. FEBS Lett 584, 4175-4180 .10.1016/j.febslet.2010.09.020
[91] Ren, F., Wang, B., Yue, T., Yun, E.Y., Ip, Y.T., and Jiang, J. (2010). Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci U S A 107, 21064-21069 .10.1073/pnas.1012759107
[92] Reya, T., Morrison, S.J., Clarke, M.F., and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 .10.1038/35102167
[93] Ribeiro, P.S., Josué, F., Wepf, A., Wehr, M.C., Rinner, O., Kelly, G., Tapon, N., and Gstaiger, M. (2010). Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol Cell 39, 521-534 .10.1016/j.molcel.2010.08.002
[94] Robinson, B.S., Huang, J., Hong, Y., and Moberg, K.H. (2010). Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20, 582-590 .10.1016/j.cub.2010.03.019
[95] Rogulja, D., Rauskolb, C., and Irvine, K.D. (2008). Morphogen control of wing growth through the Fat signaling pathway. Dev Cell 15, 309-321 .10.1016/j.devcel.2008.06.003
[96] Sansores-Garcia, L., Bossuyt, W., Wada, K., Yonemura, S., Tao, C., Sasaki, H., and Halder, G. (2011). Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J 30, 2325-2335 .10.1038/emboj.2011.157
[97] Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J.R., Zhou, D., Kreger, B.T., Vasioukhin, V., Avruch, J., Brummelkamp, T.R., . (2011). Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782-795 .10.1016/j.cell.2011.02.031
[98] Seidel, C., Schagdarsurengin, U., Blümke, K., Würl, P., Pfeifer, G.P., Hauptmann, S., Taubert, H., and Dammann, R. (2007). Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 46, 865-871 .10.1002/mc.20317
[99] Shaw, R.L., Kohlmaier, A., Polesello, C., Veelken, C., Edgar, B.A., and Tapon, N. (2010). The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147-4158 .10.1242/dev.052506
[100] Silva, E., Tsatskis, Y., Gardano, L., Tapon, N., and McNeill, H. (2006). The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway. Curr Biol 16, 2081-2089 .10.1016/j.cub.2006.09.004
[101] Silvis, M.R., Kreger, B.T., Lien, W.H., Klezovitch, O., Rudakova, G.M., Camargo, F.D., Lantz, D.M., Seykora, J.T., and 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, ra33.10.1126/scisignal.2001823
[102] Simon, M.A., Xu, A., Ishikawa, H.O., and Irvine, K.D. (2010). Modulation of fat:dachsous binding by the cadherin domain kinase four-jointed. Curr Biol 20, 811-817 .10.1016/j.cub.2010.04.016
[103] Song, H., Mak, K.K., Topol, L., Yun, K., Hu, J., Garrett, L., Chen, Y., Park, O., Chang, J., Simpson, R.M., . (2010). Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci U S A 107, 1431-1436 .10.1073/pnas.0911409107
[104] Sopko, R., Silva, E., Clayton, L., Gardano, L., Barrios-Rodiles, M., Wrana, J., Varelas, X., Arbouzova, N.I., Shaw, S., Saburi, S., . (2009). Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. Curr Biol 19, 1112-1117 .10.1016/j.cub.2009.05.049
[105] Staley, B.K., and Irvine, K.D. (2010). Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr Biol 20, 1580-1587 .10.1016/j.cub.2010.07.041
[106] Stanger, B.Z., Tanaka, A.J., and Melton, D.A. (2007). Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445, 886-891 .10.1038/nature05537
[107] Steinhardt, A.A., Gayyed, M.F., Klein, A.P., Dong, J., Maitra, A., Pan, D., Montgomery, E.A., and Anders, R.A. (2008). Expression of Yes-associated protein in common solid tumors. Hum Pathol 39, 1582-1589 .10.1016/j.humpath.2008.04.012
[108] Strazisar, M., Mlakar, V., and Glavac, D. (2009). LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer 64, 257-262 .10.1016/j.lungcan.2008.09.011
[109] Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 .10.1016/j.cell.2006.07.024
[110] Takahashi, Y., Miyoshi, Y., Takahata, C., Irahara, N., Taguchi, T., Tamaki, Y., and Noguchi, S. (2005). Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11, 1380-1385 .10.1158/1078-0432.CCR-04-1773
[111] Tamm, C., B?wer, N., and Annerén, C. (2011). Regulation of mouse embryonic stem cell self-renewal by a Yes-YAP-TEAD2 signaling pathway downstream of LIF. J Cell Sci 124, 1136-1144 .10.1242/jcs.075796
[112] Tao, W., Zhang, S., Turenchalk, G.S., Stewart, R.A., St John, M.A., Chen, W., and Xu, T. (1999). Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet 21, 177-181 .10.1038/5960
[113] Tapon, N., Harvey, K.F., Bell, D.W., Wahrer, D.C., Schiripo, T.A., Haber, D.A., and Hariharan, I.K. (2002). salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467-478 .10.1016/S0092-8674(02)00824-3
[114] Tian, W., Yu, J., Tomchick, D.R., Pan, D., and Luo, X. (2010). Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc Natl Acad Sci U S A 107, 7293-7298 .10.1073/pnas.1000293107
[115] Tontonoz, P., Hu, E., and Spiegelman, B.M. (1994). Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79, 1147-1156 .10.1016/0092-8674(94)90006-X
[116] Tyler, D.M., and Baker, N.E. (2007). Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol 305, 187-201 .10.1016/j.ydbio.2007.02.004
[117] Udan, R.S., Kango-Singh, M., Nolo, R., Tao, C., and Halder, G. (2003). Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 5, 914-920 .10.1038/ncb1050
[118] Van Hateren, N.J., Das, R.M., Hautbergue, G.M., Borycki, A.G., Placzek, M., and Wilson, S.A. (2011). FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools. Development 138, 1893-1902 .10.1242/dev.064204
[119] Varelas, X., Sakuma, R., Samavarchi-Tehrani, P., Peerani, R., Rao, B.M., Dembowy, J., Yaffe, M.B., Zandstra, P.W., and Wrana, J.L. (2008). TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10, 837-848 .10.1038/ncb1748
[120] Varelas, X., Samavarchi-Tehrani, P., Narimatsu, M., Weiss, A., Cockburn, K., Larsen, B.G., Rossant, J., and Wrana, J.L. (2010). The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev Cell 19, 831-844 .10.1016/j.devcel.2010.11.012
[121] Verma, S., Rajaratnam, J.H., Denton, J., Hoyland, J.A., and Byers, R.J. (2002). Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis. J Clin Pathol 55, 693-698 .10.1136/jcp.55.9.693
[122] Wada, K., Itoga, K., Okano, T., Yonemura, S., and Sasaki, H. (2011). Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907-3914 .10.1242/dev.070987
[123] Wang, W., Huang, J., and Chen, J. (2010). Angiomotin-like proteins associate with and negatively regulate YAP1. J Biol Chem J Biol Chem 286, 4364-4370 .
[124] Wei, X., Shimizu, T., and Lai, Z.C. (2007). Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J 26, 1772-1781 .10.1038/sj.emboj.7601630
[125] Willecke, M., Hamaratoglu, F., Kango-Singh, M., Udan, R., Chen, C.L., Tao, C., Zhang, X., and Halder, G. (2006). The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol 16, 2090-2100 .10.1016/j.cub.2006.09.005
[126] Willecke, M., Hamaratoglu, F., Sansores-Garcia, L., Tao, C., and Halder, G. (2008). Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc Natl Acad Sci U S A 105, 14897-14902 .10.1073/pnas.0805201105
[127] Wu, S., Huang, J., Dong, J., and 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 .10.1016/S0092-8674(03)00549-X
[128] Wu, S., Liu, Y., Zheng, Y., Dong, J., and Pan, D. (2008). The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14, 388-398 .10.1016/j.devcel.2008.01.007
[129] Xu, T., Wang, W., Zhang, S., Stewart, R.A., and Yu, W. (1995). Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053-1063 .
[130] Yagi, R., Kohn, M.J., Karavanova, I., Kaneko, K.J., Vullhorst, D., DePamphilis, M.L., and Buonanno, A. (2007). Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 134, 3827-3836 .10.1242/dev.010223
[131] Yu, J., Zheng, Y., Dong, J., Klusza, S., Deng, W.M., and Pan, D. (2010). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18, 288-299 .10.1016/j.devcel.2009.12.012
[132] Yue, T., Tian, A., and Jiang, J. (2012). The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the hippo signaling pathway. Dev Cell 22, 255-267 .10.1016/j.devcel.2011.12.011
[133] Zender, L., Spector, M.S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.T., Luk, J.M., Wigler, M., Hannon, G.J., . (2006). Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253-1267 .10.1016/j.cell.2006.05.030
[134] Zhang, H., Liu, C.Y., Zha, Z.Y., Zhao, B., Yao, J., Zhao, S., Xiong, Y., Lei, Q.Y., and Guan, K.L. (2009a). TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem 284, 13355-13362 .10.1074/jbc.M900843200
[135] Zhang, H., Pasolli, H.A., and Fuchs, E. (2011). Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci U S A 108, 2270-2275 .10.1073/pnas.1019603108
[136] Zhang, J., Ji, J.Y., Yu, M., Overholtzer, M., Smolen, G.A., Wang, R., Brugge, J.S., Dyson, N.J., and Haber, D.A. (2009b). YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11, 1444-1450 .10.1038/ncb1993
[137] Zhang, L., Ren, F., Zhang, Q., Chen, Y., Wang, B., and Jiang, J. (2008). The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell 14, 377-387 .10.1016/j.devcel.2008.01.006
[138] Zhang, N., Bai, H., David, K.K., Dong, J., Zheng, Y., Cai, J., Giovannini, M., Liu, P., Anders, R.A., and Pan, D. (2010). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 19, 27-38 .10.1016/j.devcel.2010.06.015
[139] Zhao, B., Li, L., Lu, Q., Wang, L.H., Liu, C.Y., Lei, Q., and Guan, K.L. (2011). Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25, 51-63 .10.1101/gad.2000111
[140] Zhao, B., Li, L., Tumaneng, K., Wang, C.Y., and Guan, K.L. (2010). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 24, 72-85 .10.1101/gad.1843810
[141] Zhao, B., Li, L., Wang, L., Wang, C.Y., Yu, J., and Guan, K.L. (2012). Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26, 54-68 .10.1101/gad.173435.111
[142] Zhao, B., Wei, X., Li, W., Udan, R.S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., Li, L., . (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21, 2747-2761 .10.1101/gad.1602907
[143] Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J.D., Wang, C.Y., Chinnaiyan, A.M., . (2008). TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 22, 1962-1971 .10.1101/gad.1664408
[144] Zhou, D., Conrad, C., Xia, F., Park, J.S., Payer, B., Yin, Y., Lauwers, G.Y., Thasler, W., Lee, J.T., Avruch, J., . (2009). Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425-438 .10.1016/j.ccr.2009.09.026
[145] Zhou, D., Zhang, Y., Wu, H., Barry, E., Yin, Y., Lawrence, E., Dawson, D., Willis, J.E., Markowitz, S.D., Camargo, F.D., . (2011a). Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc Natl Acad Sci U S A 108, E1312-E1320 .10.1073/pnas.1110428108
[146] Zhou, Z., Hao, Y., Liu, N., Raptis, L., Tsao, M.S., and Yang, X. (2011b). TAZ is a novel oncogene in non-small cell lung cancer. Oncogene 30, 2181-2186 .10.1038/onc.2010.606
[147] Ziosi, M., Baena-López, L.A., Grifoni, D., Froldi, F., Pession, A., Garoia, F., Trotta, V., Bellosta, P., Cavicchi, S., and Pession, A. (2010). dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLoS Genet 6, 6.10.1371/journal.pgen.1001140
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