转录共激活子TAZ的分子调控机制及其生物学功能的研究
摘要
研究发现转录共激活子TAZ促进细胞增殖、细胞迁移和诱导上皮细胞向间充质细胞的转化(EMT)。最近我们的研究表明TAZ受肿瘤抑制信号通路Hippo通路调控。但是作为转录共激活子,TAZ如何通过转录因子调控基因转录并行使生物学功能却还不清楚。通过实验我们发现TEAD转录因子家族成员是介导TAZ生物学功能的重要下游转录因子。阻断TEAD与TAZ的结合或者抑制细胞内源的TEAD的表达,都可以阻断了TAZ促进细胞增殖、细胞迁移和诱导上皮细胞向间充质细胞的转化的生物学功能。同时,我们还发现结缔组织生长因子(CTGF)是转录共激活子TAZ和转录因子TEAD的下游直接靶基因。我们的研究阐明了转录共激活子TAZ和转录因子TEAD的相互作用关系,以及二者的相互作用在转录共激活子TAZ行使生物学功能中的作用机制。
转录共激活子TAZ的活性受Hippo通路调控, Hippo通路的激活会促进TAZ从细胞核转运至细胞质中,从而抑制了TAZ与核转录因子的结合。我们的研究发现TAZ的蛋白质降解受SCFβ-TrCP的E3泛素连接酶的调控。β-TrCP与TAZ之间的相互作用受Hippo通路的调控。转录共激活子TAZ被激酶磷酸化后,激酶CKIε接着磷酸化TAZ,从而促进了β-TrCP与TAZ之间的结合。因此,Hippo通路不仅仅促进转录共激活子TAZ滞留在细胞质中,还促进TAZ的蛋白质降解。TAZ的依赖于蛋白酶体的降解对TAZ的生物学功能调控也有着重要作用。
转录共激活子TAZ作为受Hippo通路的调控。Hippo通路调控TAZ的活性是通过激酶LATS直接磷酸化TAZ,促进转录共激活子TAZ滞留在细胞质中并且促进TAZ的蛋白质降解。然而转录共激活子TAZ的去磷酸化调控机制以及调控TAZ活性的磷酸酶一直都不清楚。这里我们发现蛋白磷酸酶1(PP1)是调控TAZ活性的磷酸酶。PP1可以去磷酸化TAZ的Ser89位点和Ser311位点,从而促进TAZ的核定位与蛋白稳定性。进一步的,我们还发现肿瘤抑制基因ASPP2可以促进TAZ与PP1的结合,从而调控转录共激活子TAZ的去磷酸化过程。因此,PP1和ASPP2可以调控TAZ的下游靶基因的表达。这一研究阐明了PP1A和ASPP2作为转录共激活子TAZ的正调控因子,促进TAZ的生物学功能。
The TAZ transcription co-activator has been shown to promote cell proliferation and to induce epithelial-mesenchymal transition (EMT). Recently we have demonstrated that TAZ is phosphorylated and inhibited by the Hippo tumor suppressor pathway, which is altered in human cancer. The mechanism of TAZ-mediated transcription is unclear. We demonstrate here that TEAD is a key downstream transcription factor mediating the function of TAZ. Disruption of TEAD-TAZ binding or silencing of TEAD expression blocked the function of TAZ to promote cell proliferation and to induce EMT, demonstrating TEAD as a key downstream effector of TAZ. We also identified CTGF, a gene that regulates cell adhesion, proliferation and migration, as a direct target of TAZ and TEAD. Our study establishes a functional partnership between TAZ and TEAD under negative regulation by the Hippo signaling pathway.
The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box proteinβ-TrCP and ubiquitylated by the SCF/CRL1β-TrCP E3 ligase. The interaction between TAZ andβ-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1εand subsequent binding byβ-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.
The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo -TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser89 and Ser311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ dependent gene expression. Our study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the Lats kinase through TAZ dephosphorylation.
转录共激活子TAZ的活性受Hippo通路调控, Hippo通路的激活会促进TAZ从细胞核转运至细胞质中,从而抑制了TAZ与核转录因子的结合。我们的研究发现TAZ的蛋白质降解受SCFβ-TrCP的E3泛素连接酶的调控。β-TrCP与TAZ之间的相互作用受Hippo通路的调控。转录共激活子TAZ被激酶磷酸化后,激酶CKIε接着磷酸化TAZ,从而促进了β-TrCP与TAZ之间的结合。因此,Hippo通路不仅仅促进转录共激活子TAZ滞留在细胞质中,还促进TAZ的蛋白质降解。TAZ的依赖于蛋白酶体的降解对TAZ的生物学功能调控也有着重要作用。
转录共激活子TAZ作为受Hippo通路的调控。Hippo通路调控TAZ的活性是通过激酶LATS直接磷酸化TAZ,促进转录共激活子TAZ滞留在细胞质中并且促进TAZ的蛋白质降解。然而转录共激活子TAZ的去磷酸化调控机制以及调控TAZ活性的磷酸酶一直都不清楚。这里我们发现蛋白磷酸酶1(PP1)是调控TAZ活性的磷酸酶。PP1可以去磷酸化TAZ的Ser89位点和Ser311位点,从而促进TAZ的核定位与蛋白稳定性。进一步的,我们还发现肿瘤抑制基因ASPP2可以促进TAZ与PP1的结合,从而调控转录共激活子TAZ的去磷酸化过程。因此,PP1和ASPP2可以调控TAZ的下游靶基因的表达。这一研究阐明了PP1A和ASPP2作为转录共激活子TAZ的正调控因子,促进TAZ的生物学功能。
The TAZ transcription co-activator has been shown to promote cell proliferation and to induce epithelial-mesenchymal transition (EMT). Recently we have demonstrated that TAZ is phosphorylated and inhibited by the Hippo tumor suppressor pathway, which is altered in human cancer. The mechanism of TAZ-mediated transcription is unclear. We demonstrate here that TEAD is a key downstream transcription factor mediating the function of TAZ. Disruption of TEAD-TAZ binding or silencing of TEAD expression blocked the function of TAZ to promote cell proliferation and to induce EMT, demonstrating TEAD as a key downstream effector of TAZ. We also identified CTGF, a gene that regulates cell adhesion, proliferation and migration, as a direct target of TAZ and TEAD. Our study establishes a functional partnership between TAZ and TEAD under negative regulation by the Hippo signaling pathway.
The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box proteinβ-TrCP and ubiquitylated by the SCF/CRL1β-TrCP E3 ligase. The interaction between TAZ andβ-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1εand subsequent binding byβ-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.
The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo -TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser89 and Ser311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ dependent gene expression. Our study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the Lats kinase through TAZ dephosphorylation.
引文
1. Michalopoulos GK, DeFrances MC. Liver regeneration. Science.1997 Apr 4;276(5309):60-6.
2. Zhao B, Lei QY, Guan KL.2008a. The Hippo-YAP pathway:New connections between regulation of organ size and cancer. Curr Opin Cell Biol 20:638-646.
3. Kango-Singh M, Singh A.2009. Regulation of organ size:Insights from the Drosophila Hippo signaling pathway. Dev Dyn 238:1627-1637.
4. 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.
5. 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.
6. Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ, Halder G.2002. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129:5719-5730.
7. 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.
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.
9. 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.
10. 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.
11. 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.
12. 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 8:27-36.
13. Bennett FC, Harvey KF.2006. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol 16:2101-2110.
14. Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD.2006. Delineation of a Fat tumor suppressor pathway. Nat Genet 38:1142-1150.
15. 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 16:2081-2089.
16. Tyler DM, Baker NE.2007. Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol 305:187-201.
17. Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, Zhang X, Halder G.2006. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol 16:2090-2100.
18. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, et al.2007. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Dev 21:2747-2761.
19. Hao Y, Chun A, Cheung K, Rashidi B, Yang X.2008. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 283:5496-5509.
20. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. 2008. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28:2426-2436.
21. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR.2007. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054-2060.
22. 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.
23. Shimizu T, Ho LL, Lai ZC.2008. The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178: 957-965.
24. Wei X, Shimizu T, Lai ZC.2007. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J 26:1772-1781.
25. Edgar BA.2006. From cell structure to transcription:Hippo forges a new path. Cell 124:267-273.
26. Nolo R, Morrison CM, Tao C, Zhang X, Halder G.2006. The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr Biol 16:1895-1904.
27. Thompson BJ, Cohen SM.2006. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126: 767-774.
28 Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A.2008. SCALLOPED interacts with YORKIE, the nuclear effector of the Hippo tumor-suppressor pathway in Drosophila. Curr Biol 18:435-441.
29. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, et al.2008b. TEAD mediates YAP-dependent gene induction and growth control. Genes & Dev 22:1962-1971.
30. Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J.2008. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell 14:377-387.
31. Wu S, Liu Y, Zheng Y, Dong J, Pan D.2008. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14:388-398.
32. Pellock BJ, Buff E, White K, Hariharan IK.2007. The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling. Dev Biol 304:102-115.
33. Maitra S, Kulikauskas RM, Gavilan H, Fehon RG.2006. The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol 16:702-709.
34. Yu J, Zheng Y, Dong J, Klusza S, Deng WM, 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.
35. Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N.2010. Kibra is a regulator of the salvador/warts/hippo signaling network. Dev Cell 18:300-308.
36. Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H.2010. The WW domain protein Kibra acts upstream of hippo in Drosophila. Dev Cell 18: 309-316.
37. Rogulja D, Rauskolb C, Irvine KD.2008. Morphogen control of wing growth through the Fat signaling pathway. Dev Cell 15:309-321.
38. Willecke M, Hamaratoglu F, Sansores-Garcia L, Tao C, Halder G.2008. Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc Natl Acad Sci 105:14897-14902.
39. Mao Y, Kucuk B, Irvine KD.2009. Drosophila lowfat, a novel modulator of Fat signaling. Development 136:3223-3233.
40. Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, Chernoff J, Clark EA, Krebs EG.1998. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 17:2224-2234.
41. Lee KK, Yonehara S.2002. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J Biol Chem 277:12351-12358.
42. Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J.2002. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol 12:253-265.
43. Oh HJ, Lee KK, Song SJ, Jin MS, Song MS, Lee JH, Im CR, Lee JO, Yonehara S, Lim DS.2006. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res 66:2562-2569.
44. Praskova M, Khoklatchev A, Ortiz-Vega S, 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.
45. O'Neill E, Rushworth L, Baccarini M, Kolch W.2004. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306: 2267-2270.
46. Densham RM, O'Neill E, Munro J, Konig I, Anderson K, Kolch W, Olson MF. 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.
47. Anguera MC, Liu M, Avruch J, Lee JT.Characterization of two Mstl-deficient mouse models.Dev Dyn.2008 Nov;237(11):3424-34.
48. Dong Y, Du X, Ye J, Han M, Xu T, Zhuang Y, Tao W.A cell-intrinsic role for Mstl in regulating thymocyte egress.J Immunol.2009 Sep 15;183(6):3865-72. Epub 2009 Aug 19.
49. Zhou D, Medoff BD, Chen L, Li L, Zhang XF, Praskova M, Liu M, Landry A, Blumberg RS, Boussiotis VA, Xavier R, Avruch J.The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells.Proc Natl Acad Sci U S A.2008 Dec 23;105(51):20321-6. Epub 2008 Dec 10.
50. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, et al.2009. Mstl and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yapl oncogene. Cancer Cell 16:425-438.
51. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, Halder G, Finegold MJ, Lee JS, et al.2010. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci 107:1437-1442.
52. Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, Chen Y, Park O, Chang J, Simpson RM, et al.2010. Mammalian Mstl and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Nat1 Acad Sci 107:1431-1436.
53. Callus BA, Verhagen AM, Vaux DL.2006. Association of mammalian sterile twenty kinases, Mstl and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J 273:4264-4276.
54. Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, et al.2008. A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J 27:1231-1242.
55. Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH. 2005. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Latsl. Oncogene 24:2076-2086.
56. St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T.1999. Mice deficient of Latsl develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21:182-186.
57. Yabuta N, Okada N, Ito A, Hosomi T, Nishihara S, Sasayama Y, Fujimori A, Okuzaki D, Zhao H, Ikawa M, et al.2007. Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem 282:19259-19271.
58. McPherson JP, Tamblyn L, Elia A, Migon E, Shehabeldin A, Matysiak-Zablocki E, Lemmers B, Salmena L, Hakem A, Fish J, et al.2004. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J 23:3677-3688.
59. Zhang J, Smolen GA, Haber DA.2008. Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. Cancer Res 68:2789-2794.
60. Weiquan Li, Lizhong Wang, Hiroto Katoh, Runhua Liu, Pan Zheng, and Yang Liu.Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers. Cancer Res March 15,2011 71; 2162
61. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, et al.2006. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124:1169-1181.
62. Lee KH, Goan YG, Hsiao M, Lee CH, Jian SH, Lin JT, Chen YL, Lu PJ.2009. MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Exp Cell Res 315:2529-2538.
63. Cho WJ, Shin JM, Kim JS, Lee MR, Hong KS, Lee JH, Koo KH, Park JW, Kim KS.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.
64. Chow A, Hao Y, Yang X.2010. Molecular characterization of human homologs of yeast MOB1. Int J Cancer 126:2079-2089.
65. Praskova M, Xia F, Avruch J.2008. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 18:311-321.
66. Hergovich A, Schmitz D, Hemmings BA.2006. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem Biophys Res Commun 345:50-58.
67. Ho LL, Wei X, Shimizu T, Lai ZC.2009. Mob as tumor suppressor is activated at the cell membrane to control tissue growth and organ size in Drosophila. Dev Biol 337:274-283.
68. Stegert MR, Hergovich A, Tamaskovic R, Bichsel SJ, Hemmings BA.2005. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol Cell Biol 25: 11019-11029.
69. Lau YK, Murray LB, Houshmandi SS, Xu Y, Gutmann DH, Yu Q.2008. Merlin is a potent inhibitor of glioma growth. Cancer Res 68:5733-5742.
70. Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, et al.2008. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis 29:2139-2146.
71. Nailing Zhang,Haibo Bai,Karen K. David,Jixin Dong,Yonggang Zheng,Jing Cai,Marco Giovannini,Pentao Liu,Robert A. Anders,and Duojia Pan. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals.Dev Cell.2010 July 20; 19(1):27-38.
72. Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B, Engel C, Moeller MJ, Englert C, Bollig F, et al.2009. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci 106:8579-8584.
73. Komuro A, Nagai M, Navin NE, Sudol M.2003. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem 278:33334-33341.
74. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, et al.2000. TAZ:A novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 19:6778-6791.
75. Morin-Kensicki EM, Boone BN, Ho well M, Stonebraker JR, Teed J, Alb JG, Magnuson TR, O'Neal W, Milgram SL.2006. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol Cell Biol 26:77-87.
76. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
77. Tian, Y, R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
78. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5): 1631-1636.
79. Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA.2009. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11: 1444-1450.
80. Ren F, Zhang L, Jiang J.2009. Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev Biol 337:303-312.
81. Li Z, Zhao B, Wang P, Chen F, Dong Z, Yang H, Guan KL, Xu Y.2010. Structural insights into the YAP and TEAD complex. Genes & Dev 24:235-240.
82. Chen L, Chan SW, Zhang X, Walsh M, Lim CJ, Hong W, Song H.2010. Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes & Dev 24:290-300.
83. Fossdal R, Jonasson F, Kristjansdottir GT, Kong A, Stefansson H, Gosh S, Gulcher JR, 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.
84. Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. 2009. Neurofibromatosis type 2. Lancet 373:1974-1986.
85. Kosaka Y, Mimori K, Tanaka F, Inoue H, Watanabe M, Mori M.2007. Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer. Int J Oncol 31:333-338.
86. Hisaoka M, Tanaka A, Hashimoto H.2002. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest 82: 1427-1435.
87. Jimenez-Velasco A, Roman-Gomez J, Agirre X, Barrios M, Navarro G, Vazquez I, Prosper F, Torres A, 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.
88. Chakraborty S, Khare S, Dorairaj SK, Prabhakaran VC, Prakash DR, Kumar A. 2007. Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. Genomics 90:344-353.
89. Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, 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.
90. Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D.2006. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56:450-458.
91. Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, Lugli A.2007. Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod Pathol 20:331-338.
92. Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S, Taubert H, Dammann R.2007. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 46:865-871.
93. Baldwin C, Garnis C, Zhang L, Rosin MP, Lam WL.2005. Multiple microalterations detected at high frequency in oral cancer. Cancer Res 65: 7561-7567.
94. Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM.2009. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes & Dev 23:2729-2741.
95. Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, Janssen I, Giangaspero F, Forni M, Finocchiaro G, et al.2006. Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24:5223-5233.
96. Snijders AM, Schmidt BL, Fridlyand J, Dekker N, Pinkel D, Jordan RC, Albertson DG.2005. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene 24: 4232-4242.
97. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA.2006. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci 103: 12405-12410.
98. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, et al.2006. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253-1267.
99. Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA.2008. Expression of Yes-associated protein in common solid tumors. Hum Pathol 39:1582-1589.
100. Xu MZ, Yao TJ, Lee NP, Ng 10, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM.2009. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115:4576-4585.
101. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y and Guan KL:TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28:2426-36,2008.
102. Trigiante G and Lu X:ASPP [corrected] and cancer. Nat Rev Cancer 6: 217-26,2006.
103. Aylon Y, Ofir-Rosenfeld Y, Yabuta N, Lapi E, Nojima H, Lu X and Oren M:The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1. Genes Dev 24:2420-9,2010.
104. Vigneron AM, Ludwig RL and Vousden KH:Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev 24:2430-9,2010.
105. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J and Wrana JL:The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19:831-44,2010.
106. Tian Y, Li D, Dahl J, You J and Benjamin T:Identification of TAZ as a binding partner of the polyomavirus T antigens. J Virol 78:12657-64,2004.
107. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q and Guan KL:Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25: 51-63,2011.
108. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C and Hong W:Hippo Pathway-independent Restriction of TAZ and YAP by Angiomotin. J Biol Chem 286:7018-26,2011.
109. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M and Gettemans J:TAZ interacts with zonula occludens-1 and-2 proteins in a PDZ-1 dependent manner. FEBS Lett 584:4175-80,2010.
110. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J and Wrana JL:The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19:831-44,2010.
111.Grzeschik NA, Parsons LM, Allott ML, Harvey KF and Richardson HE: Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20:573-81,2010.
112. Robinson BS, Huang J, Hong Y and Moberg KH:Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20:582-90,2010.
113. Cui CB, Cooper LF, Yang X, Karsenty G and Aukhil I:Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol 23: 1004-13,2003.
114. Park KS, Whitsett JA, Di Palma T, Hong JH, Yaffe MB and Zannini M: TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. J Biol Chem 279:17384-90,2004.
115. Murakami M, Nakagawa M, Olson EN and Nakagawa O: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 102:18034-9,2005.
116. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N and Yaffe MB: TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074-8,2005.
117. Murakami M, Tominaga J, Makita R, Uchijima Y, Kurihara Y, Nakagawa O, Asano T and Kurihara H:Transcriptional activity of Pax3 is co-activated by TAZ. Biochem Biophys Res Commun 339:533-9,2006.
118. Jeong H, Bae S, An SY, Byun MR, Hwang JH, Yaffe MB, Hong JH and Hwang ES:TAZ as a novel enhancer of MyoD-mediated myogenic differentiation. FASEB J 24:3310-20,2010.
119. Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D, Pappalardo A, Mascia A and Zannini M:TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Exp Cell Res 315:162-75,2009.
120. Kang HS, Beak JY, Kim YS, Herbert R and Jetten AM:Glis3 is associated with primary cilia and Wwtrl/TAZ and implicated in polycystic kidney disease. Mol Cell Biol 29:2556-69,2009.
121. Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW and Wrana JL:TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10:837-48,2008.
122. Mahoney WM, Jr., Hong JH, Yaffe MB and Farrance IK:The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. Biochem J 388:217-25,2005.
123. Eda H, Aoki K, Marumo K, Fujii K and Ohkawa K:FGF-2 signaling induces downregulation of TAZ protein in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 366:471-5,2008.
124. Liu Q, Gu X, Zhao Y, Zhang J, Meng Q, Xu G, Hu X and Li N:Pig large tumor suppressor 2 (Lats2), a novel gene that may regulate the fat reduction in adipocyte. BMB Rep 43:97-102,2010.
125. Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D and Massague J: Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139:757-69,2009.
126. Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A and Mauviel A:Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21:4879-84, 2002.
127. Green DR and Kroemer G:Cytoplasmic functions of the tumour suppressor p53. Nature 458:1127-30,2009.
128. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL and Attisano L:The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell 18:579-91,2010.
129. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, Deruiter MC, Breuning MH, de Heer E and Peters DJ:Lowering of Pkdl expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069-77,2004.
130. Pritchard L, Sloane-Stanley JA, Sharpe JA, Aspinwall R, Lu W, Buckle V, Strmecki L, Walker D, Ward CJ, Alpers CE, Zhou J, Wood WG and Harris PC:A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9:2617-27,2000.
131. Duning K, Rosenbusch D, Schluter MA, Tian Y, Kunzelmann K, Meyer N, Schulze U, Markoff A, Pavenstadt H and Weide T:Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS 1-associated tight junction protein. J Biol Chem 285:33584-8,2010.
132. Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A, Vandewalle A and Perret C:Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20:5972-81,2001.
133. Qian CN, Knol J, Igarashi P, Lin F, Zylstra U, Teh BT and Williams BO: Cystic renal neoplasia following conditional inactivation of ape in mouse renal tubular epithelium. J Biol Chem 280:3938-45,2005.
134. Fan S, Hurd TW, Liu CJ, Straight SW, Weimbs T, Hurd EA, Domino SE and Margolis B:Polarity proteins control ciliogenesis via kinesin motor interactions. Curr Biol 14:1451-61,2004.
1.Chu CY, et al.Connective tissue growth factor (CTGF) and cancer progression.J Biomed Sci.2008 Nov;15(6):675-85.
2.Lei QY, et al.TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol.2008 Apr;28(7):2426-36.
3. Chan, S. W., C. J. Lim, et al. (2008). "A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells." Cancer Res 68(8):2592-2598.
4. Hinestrosa, M. C., K. Dickersin, et al. (2007). "Shaping the future of biomarker research in breast cancer to ensure clinical relevance." Nat Rev Cancer 7(4):309-315.
5. Evans, D. G. (2009). "Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type Ⅱ]." Genet Med 11(9): 599-610.
6. Li, Z., B. Zhao, et al. (2010). "Structural insights into the YAP and TEAD complex." Genes Dev 24(3):235-240.
7. Chen, L., P. G. Loh, et al. (2010). "Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway." Protein Cell 1(12): 1073-1083.
8. Varelas, X., R. Sakuma, et al. (2008). "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal." Nat Cell Biol 10(7): 837-848.
9. Zhao, B., X. Wei, et al. (2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control." Genes Dev 21(21):2747-2761.
10. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
11. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
12. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5):1631-1636.
13. Chen, Z., G. A. Friedrich, et al. (1994). "Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice." Genes Dev 8(19):2293-2301.
14. Yagi, R., M. J. Kohn, et al. (2007). "Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development." Development 134(21):3827-3836.
1. Lei, Q. Y., H. Zhang, et al. (2008). "TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway." Mol Cell Biol 28(7):2426-2436.
2. Ribeiro, P. S., F. Josue, et al. (2010). "Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling." Mol Cell 39(4):521-534.
3. Cohen, P. (1989). "The structure and regulation of protein phosphatases." Annu Rev Biochem 58:453-508.
4. Suganuma, M., H. Fujiki, et al. (1990). "Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin." Cancer Res 50(12): 3521-3525.
5. Helps, N. R., H. M. Barker, et al. (1995). "Protein phosphatase 1 interacts with p53BP2, a protein which binds to the tumour suppressor p53." FEBS Lett 377(3): 295-300.
6. Espanel, X. and M. Sudol (2001). "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains." J Biol Chem 276(17): 14514-14523.
7. Egloff, M. P., D. F. Johnson, et al. (1997). "Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1." EMBO J 16(8): 1876-1887.
8. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physio 1 Renal Physiol 294(3):F542-553.
9. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
10. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1." Proc Natl Acad Sci U S A 104(5):1631-1636.
11. Kanai, F., P. A. Marignani, et al. (2000). "TAZ:a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins." EMBO J 19(24):6778-6791.
12. Mitsuhashi, S., H. Shima, et al. (2003). "Usage of tautomycetin, a novel inhibitor of protein phosphatase 1 (PP1), reveals that PP1 is a positive regulator of Raf-1 in vivo." J Biol Chem 278(1):82-88.
13. Schlegelmilch, K., M. Mohseni, et al. (2011). "Yap1 Acts Downstream of alpha-Catenin to Control Epidermal Proliferation." Cell 144(5):782-795.
14. Hakuno, F., S. Kurihara, et al. (2007). "53BP2S, interacting with insulin receptor substrates, modulates insulin signaling." J Biol Chem 282(52):37747-37758.
15. Fernandez, L. A., P. A. Northcott, et al. (2009). "YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation." Genes Dev 23(23):2729-2741.
16. Vives, V., J. Su, et al. (2006). "ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth." Genes Dev 20(10):1262-1267.
17. Bergamaschi, D., Y. Samuels, et al. (2004). "ASPP1 and ASPP2:common activators of p53 family members." Mol Cell Biol 24(3):1341-1350.
18. Chen, Y., W. Liu, et al. (2003). "ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis." J Neurochem 85(3):801-809.
19. Vigneron, A. M., R. L. Ludwig, et al. (2010). "Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP." Genes Dev 24(21):2430-2439.
1. Chan, S. W., C. J. Lim, et al. (2008). "A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells." Cancer Res 68(8):2592-2598.
2. Hart, M., J. P. Concordet, et al. (1999). "The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell." Curr Biol 9(4): 207-210.
3. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
4. Frescas, D. and M. Pagano (2008). "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP:tipping the scales of cancer." Nat Rev Cancer 8(6):438-449.
5. Kalousi, A., I. Mylonis, et al. (2010). "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1." J Cell Sci 123(Pt 17):2976-2986.
6. Behrend, L., D. M. Milne, et al. (2000). "IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects." Oncogene 19(47):5303-5313.
7. Rena, G., J. Bain, et al. (2004). "D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXOla." EMBO Rep 5(1):60-65.
8. Morin-Kensicki, E. M., B. N. Boone, et al. (2006). "Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65." Mol Cell Biol 26(1):77-87.
9. Sawada, A., H. Kiyonari, et al. (2008). "Redundant roles of Teadl and Tead2 in notochord development and the regulation of cell proliferation and survival." Mol Cell Biol 28(10):3177-3189.
10. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
11. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5):1631-1636.
12. Zhao, B., X.Wei, et al. (2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control." Genes Dev 21(21):2747-2761.
13. Zhou, Z., Y.Hao, et al. (2011). "TAZ is a novel oncogene in non-small cell lung cancer." Oncogene.
14. de Cristofaro, T., T. Di Palma, et al. (2011). "TAZ/WWTR1 is overexpressed in papillary thyroid carcinoma." Eur J Cancer 47(6):926-933.
15. Overholtzer, M., J. Zhang, et al. (2006). "Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon." Proc Natl Acad Sci U S A 103(33):12405-12410.
2. Zhao B, Lei QY, Guan KL.2008a. The Hippo-YAP pathway:New connections between regulation of organ size and cancer. Curr Opin Cell Biol 20:638-646.
3. Kango-Singh M, Singh A.2009. Regulation of organ size:Insights from the Drosophila Hippo signaling pathway. Dev Dyn 238:1627-1637.
4. 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.
5. 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.
6. Kango-Singh M, Nolo R, Tao C, Verstreken P, Hiesinger PR, Bellen HJ, Halder G.2002. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129:5719-5730.
7. 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.
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.
9. 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.
10. 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.
11. 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.
12. 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 8:27-36.
13. Bennett FC, Harvey KF.2006. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr Biol 16:2101-2110.
14. Cho E, Feng Y, Rauskolb C, Maitra S, Fehon R, Irvine KD.2006. Delineation of a Fat tumor suppressor pathway. Nat Genet 38:1142-1150.
15. 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 16:2081-2089.
16. Tyler DM, Baker NE.2007. Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol 305:187-201.
17. Willecke M, Hamaratoglu F, Kango-Singh M, Udan R, Chen CL, Tao C, Zhang X, Halder G.2006. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr Biol 16:2090-2100.
18. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, et al.2007. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Dev 21:2747-2761.
19. Hao Y, Chun A, Cheung K, Rashidi B, Yang X.2008. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 283:5496-5509.
20. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. 2008. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28:2426-2436.
21. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR.2007. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054-2060.
22. 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.
23. Shimizu T, Ho LL, Lai ZC.2008. The mob as tumor suppressor gene is essential for early development and regulates tissue growth in Drosophila. Genetics 178: 957-965.
24. Wei X, Shimizu T, Lai ZC.2007. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J 26:1772-1781.
25. Edgar BA.2006. From cell structure to transcription:Hippo forges a new path. Cell 124:267-273.
26. Nolo R, Morrison CM, Tao C, Zhang X, Halder G.2006. The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr Biol 16:1895-1904.
27. Thompson BJ, Cohen SM.2006. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126: 767-774.
28 Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A.2008. SCALLOPED interacts with YORKIE, the nuclear effector of the Hippo tumor-suppressor pathway in Drosophila. Curr Biol 18:435-441.
29. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, et al.2008b. TEAD mediates YAP-dependent gene induction and growth control. Genes & Dev 22:1962-1971.
30. Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J.2008. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell 14:377-387.
31. Wu S, Liu Y, Zheng Y, Dong J, Pan D.2008. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell 14:388-398.
32. Pellock BJ, Buff E, White K, Hariharan IK.2007. The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling. Dev Biol 304:102-115.
33. Maitra S, Kulikauskas RM, Gavilan H, Fehon RG.2006. The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol 16:702-709.
34. Yu J, Zheng Y, Dong J, Klusza S, Deng WM, 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.
35. Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N.2010. Kibra is a regulator of the salvador/warts/hippo signaling network. Dev Cell 18:300-308.
36. Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H.2010. The WW domain protein Kibra acts upstream of hippo in Drosophila. Dev Cell 18: 309-316.
37. Rogulja D, Rauskolb C, Irvine KD.2008. Morphogen control of wing growth through the Fat signaling pathway. Dev Cell 15:309-321.
38. Willecke M, Hamaratoglu F, Sansores-Garcia L, Tao C, Halder G.2008. Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc Natl Acad Sci 105:14897-14902.
39. Mao Y, Kucuk B, Irvine KD.2009. Drosophila lowfat, a novel modulator of Fat signaling. Development 136:3223-3233.
40. Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, Chernoff J, Clark EA, Krebs EG.1998. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 17:2224-2234.
41. Lee KK, Yonehara S.2002. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J Biol Chem 277:12351-12358.
42. Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J.2002. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol 12:253-265.
43. Oh HJ, Lee KK, Song SJ, Jin MS, Song MS, Lee JH, Im CR, Lee JO, Yonehara S, Lim DS.2006. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res 66:2562-2569.
44. Praskova M, Khoklatchev A, Ortiz-Vega S, 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.
45. O'Neill E, Rushworth L, Baccarini M, Kolch W.2004. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306: 2267-2270.
46. Densham RM, O'Neill E, Munro J, Konig I, Anderson K, Kolch W, Olson MF. 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.
47. Anguera MC, Liu M, Avruch J, Lee JT.Characterization of two Mstl-deficient mouse models.Dev Dyn.2008 Nov;237(11):3424-34.
48. Dong Y, Du X, Ye J, Han M, Xu T, Zhuang Y, Tao W.A cell-intrinsic role for Mstl in regulating thymocyte egress.J Immunol.2009 Sep 15;183(6):3865-72. Epub 2009 Aug 19.
49. Zhou D, Medoff BD, Chen L, Li L, Zhang XF, Praskova M, Liu M, Landry A, Blumberg RS, Boussiotis VA, Xavier R, Avruch J.The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells.Proc Natl Acad Sci U S A.2008 Dec 23;105(51):20321-6. Epub 2008 Dec 10.
50. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, et al.2009. Mstl and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yapl oncogene. Cancer Cell 16:425-438.
51. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, Wang Y, Halder G, Finegold MJ, Lee JS, et al.2010. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci 107:1437-1442.
52. Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, Chen Y, Park O, Chang J, Simpson RM, et al.2010. Mammalian Mstl and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Nat1 Acad Sci 107:1431-1436.
53. Callus BA, Verhagen AM, Vaux DL.2006. Association of mammalian sterile twenty kinases, Mstl and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J 273:4264-4276.
54. Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, Oh HJ, Lee SH, Kong YY, Kim JM, et al.2008. A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J 27:1231-1242.
55. Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH. 2005. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Latsl. Oncogene 24:2076-2086.
56. St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T.1999. Mice deficient of Latsl develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21:182-186.
57. Yabuta N, Okada N, Ito A, Hosomi T, Nishihara S, Sasayama Y, Fujimori A, Okuzaki D, Zhao H, Ikawa M, et al.2007. Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem 282:19259-19271.
58. McPherson JP, Tamblyn L, Elia A, Migon E, Shehabeldin A, Matysiak-Zablocki E, Lemmers B, Salmena L, Hakem A, Fish J, et al.2004. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J 23:3677-3688.
59. Zhang J, Smolen GA, Haber DA.2008. Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. Cancer Res 68:2789-2794.
60. Weiquan Li, Lizhong Wang, Hiroto Katoh, Runhua Liu, Pan Zheng, and Yang Liu.Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers. Cancer Res March 15,2011 71; 2162
61. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, et al.2006. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124:1169-1181.
62. Lee KH, Goan YG, Hsiao M, Lee CH, Jian SH, Lin JT, Chen YL, Lu PJ.2009. MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Exp Cell Res 315:2529-2538.
63. Cho WJ, Shin JM, Kim JS, Lee MR, Hong KS, Lee JH, Koo KH, Park JW, Kim KS.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.
64. Chow A, Hao Y, Yang X.2010. Molecular characterization of human homologs of yeast MOB1. Int J Cancer 126:2079-2089.
65. Praskova M, Xia F, Avruch J.2008. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 18:311-321.
66. Hergovich A, Schmitz D, Hemmings BA.2006. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem Biophys Res Commun 345:50-58.
67. Ho LL, Wei X, Shimizu T, Lai ZC.2009. Mob as tumor suppressor is activated at the cell membrane to control tissue growth and organ size in Drosophila. Dev Biol 337:274-283.
68. Stegert MR, Hergovich A, Tamaskovic R, Bichsel SJ, Hemmings BA.2005. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol Cell Biol 25: 11019-11029.
69. Lau YK, Murray LB, Houshmandi SS, Xu Y, Gutmann DH, Yu Q.2008. Merlin is a potent inhibitor of glioma growth. Cancer Res 68:5733-5742.
70. Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, Yatabe Y, Hasegawa Y, Shimokata K, Horio Y, et al.2008. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis 29:2139-2146.
71. Nailing Zhang,Haibo Bai,Karen K. David,Jixin Dong,Yonggang Zheng,Jing Cai,Marco Giovannini,Pentao Liu,Robert A. Anders,and Duojia Pan. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals.Dev Cell.2010 July 20; 19(1):27-38.
72. Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B, Engel C, Moeller MJ, Englert C, Bollig F, et al.2009. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci 106:8579-8584.
73. Komuro A, Nagai M, Navin NE, Sudol M.2003. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem 278:33334-33341.
74. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, et al.2000. TAZ:A novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 19:6778-6791.
75. Morin-Kensicki EM, Boone BN, Ho well M, Stonebraker JR, Teed J, Alb JG, Magnuson TR, O'Neal W, Milgram SL.2006. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol Cell Biol 26:77-87.
76. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
77. Tian, Y, R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
78. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5): 1631-1636.
79. Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA.2009. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 11: 1444-1450.
80. Ren F, Zhang L, Jiang J.2009. Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev Biol 337:303-312.
81. Li Z, Zhao B, Wang P, Chen F, Dong Z, Yang H, Guan KL, Xu Y.2010. Structural insights into the YAP and TEAD complex. Genes & Dev 24:235-240.
82. Chen L, Chan SW, Zhang X, Walsh M, Lim CJ, Hong W, Song H.2010. Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes & Dev 24:290-300.
83. Fossdal R, Jonasson F, Kristjansdottir GT, Kong A, Stefansson H, Gosh S, Gulcher JR, 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.
84. Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. 2009. Neurofibromatosis type 2. Lancet 373:1974-1986.
85. Kosaka Y, Mimori K, Tanaka F, Inoue H, Watanabe M, Mori M.2007. Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer. Int J Oncol 31:333-338.
86. Hisaoka M, Tanaka A, Hashimoto H.2002. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest 82: 1427-1435.
87. Jimenez-Velasco A, Roman-Gomez J, Agirre X, Barrios M, Navarro G, Vazquez I, Prosper F, Torres A, 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.
88. Chakraborty S, Khare S, Dorairaj SK, Prabhakaran VC, Prakash DR, Kumar A. 2007. Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. Genomics 90:344-353.
89. Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, 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.
90. Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D.2006. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci Res 56:450-458.
91. Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, Lugli A.2007. Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer. Mod Pathol 20:331-338.
92. Seidel C, Schagdarsurengin U, Blumke K, Wurl P, Pfeifer GP, Hauptmann S, Taubert H, Dammann R.2007. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 46:865-871.
93. Baldwin C, Garnis C, Zhang L, Rosin MP, Lam WL.2005. Multiple microalterations detected at high frequency in oral cancer. Cancer Res 65: 7561-7567.
94. Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM.2009. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes & Dev 23:2729-2741.
95. Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, Janssen I, Giangaspero F, Forni M, Finocchiaro G, et al.2006. Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24:5223-5233.
96. Snijders AM, Schmidt BL, Fridlyand J, Dekker N, Pinkel D, Jordan RC, Albertson DG.2005. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene 24: 4232-4242.
97. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA.2006. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci 103: 12405-12410.
98. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, et al.2006. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253-1267.
99. Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, Montgomery EA, Anders RA.2008. Expression of Yes-associated protein in common solid tumors. Hum Pathol 39:1582-1589.
100. Xu MZ, Yao TJ, Lee NP, Ng 10, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM.2009. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115:4576-4585.
101. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y and Guan KL:TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 28:2426-36,2008.
102. Trigiante G and Lu X:ASPP [corrected] and cancer. Nat Rev Cancer 6: 217-26,2006.
103. Aylon Y, Ofir-Rosenfeld Y, Yabuta N, Lapi E, Nojima H, Lu X and Oren M:The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1. Genes Dev 24:2420-9,2010.
104. Vigneron AM, Ludwig RL and Vousden KH:Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev 24:2430-9,2010.
105. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J and Wrana JL:The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19:831-44,2010.
106. Tian Y, Li D, Dahl J, You J and Benjamin T:Identification of TAZ as a binding partner of the polyomavirus T antigens. J Virol 78:12657-64,2004.
107. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q and Guan KL:Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 25: 51-63,2011.
108. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C and Hong W:Hippo Pathway-independent Restriction of TAZ and YAP by Angiomotin. J Biol Chem 286:7018-26,2011.
109. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M and Gettemans J:TAZ interacts with zonula occludens-1 and-2 proteins in a PDZ-1 dependent manner. FEBS Lett 584:4175-80,2010.
110. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, Rossant J and Wrana JL:The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell 19:831-44,2010.
111.Grzeschik NA, Parsons LM, Allott ML, Harvey KF and Richardson HE: Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20:573-81,2010.
112. Robinson BS, Huang J, Hong Y and Moberg KH:Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol 20:582-90,2010.
113. Cui CB, Cooper LF, Yang X, Karsenty G and Aukhil I:Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ. Mol Cell Biol 23: 1004-13,2003.
114. Park KS, Whitsett JA, Di Palma T, Hong JH, Yaffe MB and Zannini M: TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. J Biol Chem 279:17384-90,2004.
115. Murakami M, Nakagawa M, Olson EN and Nakagawa O: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 102:18034-9,2005.
116. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N and Yaffe MB: TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309:1074-8,2005.
117. Murakami M, Tominaga J, Makita R, Uchijima Y, Kurihara Y, Nakagawa O, Asano T and Kurihara H:Transcriptional activity of Pax3 is co-activated by TAZ. Biochem Biophys Res Commun 339:533-9,2006.
118. Jeong H, Bae S, An SY, Byun MR, Hwang JH, Yaffe MB, Hong JH and Hwang ES:TAZ as a novel enhancer of MyoD-mediated myogenic differentiation. FASEB J 24:3310-20,2010.
119. Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D, Pappalardo A, Mascia A and Zannini M:TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Exp Cell Res 315:162-75,2009.
120. Kang HS, Beak JY, Kim YS, Herbert R and Jetten AM:Glis3 is associated with primary cilia and Wwtrl/TAZ and implicated in polycystic kidney disease. Mol Cell Biol 29:2556-69,2009.
121. Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW and Wrana JL:TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10:837-48,2008.
122. Mahoney WM, Jr., Hong JH, Yaffe MB and Farrance IK:The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. Biochem J 388:217-25,2005.
123. Eda H, Aoki K, Marumo K, Fujii K and Ohkawa K:FGF-2 signaling induces downregulation of TAZ protein in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 366:471-5,2008.
124. Liu Q, Gu X, Zhao Y, Zhang J, Meng Q, Xu G, Hu X and Li N:Pig large tumor suppressor 2 (Lats2), a novel gene that may regulate the fat reduction in adipocyte. BMB Rep 43:97-102,2010.
125. Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D and Massague J: Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139:757-69,2009.
126. Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A and Mauviel A:Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21:4879-84, 2002.
127. Green DR and Kroemer G:Cytoplasmic functions of the tumour suppressor p53. Nature 458:1127-30,2009.
128. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL and Attisano L:The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell 18:579-91,2010.
129. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, Deruiter MC, Breuning MH, de Heer E and Peters DJ:Lowering of Pkdl expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069-77,2004.
130. Pritchard L, Sloane-Stanley JA, Sharpe JA, Aspinwall R, Lu W, Buckle V, Strmecki L, Walker D, Ward CJ, Alpers CE, Zhou J, Wood WG and Harris PC:A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9:2617-27,2000.
131. Duning K, Rosenbusch D, Schluter MA, Tian Y, Kunzelmann K, Meyer N, Schulze U, Markoff A, Pavenstadt H and Weide T:Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS 1-associated tight junction protein. J Biol Chem 285:33584-8,2010.
132. Saadi-Kheddouci S, Berrebi D, Romagnolo B, Cluzeaud F, Peuchmaur M, Kahn A, Vandewalle A and Perret C:Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20:5972-81,2001.
133. Qian CN, Knol J, Igarashi P, Lin F, Zylstra U, Teh BT and Williams BO: Cystic renal neoplasia following conditional inactivation of ape in mouse renal tubular epithelium. J Biol Chem 280:3938-45,2005.
134. Fan S, Hurd TW, Liu CJ, Straight SW, Weimbs T, Hurd EA, Domino SE and Margolis B:Polarity proteins control ciliogenesis via kinesin motor interactions. Curr Biol 14:1451-61,2004.
1.Chu CY, et al.Connective tissue growth factor (CTGF) and cancer progression.J Biomed Sci.2008 Nov;15(6):675-85.
2.Lei QY, et al.TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol.2008 Apr;28(7):2426-36.
3. Chan, S. W., C. J. Lim, et al. (2008). "A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells." Cancer Res 68(8):2592-2598.
4. Hinestrosa, M. C., K. Dickersin, et al. (2007). "Shaping the future of biomarker research in breast cancer to ensure clinical relevance." Nat Rev Cancer 7(4):309-315.
5. Evans, D. G. (2009). "Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type Ⅱ]." Genet Med 11(9): 599-610.
6. Li, Z., B. Zhao, et al. (2010). "Structural insights into the YAP and TEAD complex." Genes Dev 24(3):235-240.
7. Chen, L., P. G. Loh, et al. (2010). "Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway." Protein Cell 1(12): 1073-1083.
8. Varelas, X., R. Sakuma, et al. (2008). "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal." Nat Cell Biol 10(7): 837-848.
9. Zhao, B., X. Wei, et al. (2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control." Genes Dev 21(21):2747-2761.
10. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
11. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
12. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5):1631-1636.
13. Chen, Z., G. A. Friedrich, et al. (1994). "Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice." Genes Dev 8(19):2293-2301.
14. Yagi, R., M. J. Kohn, et al. (2007). "Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development." Development 134(21):3827-3836.
1. Lei, Q. Y., H. Zhang, et al. (2008). "TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway." Mol Cell Biol 28(7):2426-2436.
2. Ribeiro, P. S., F. Josue, et al. (2010). "Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling." Mol Cell 39(4):521-534.
3. Cohen, P. (1989). "The structure and regulation of protein phosphatases." Annu Rev Biochem 58:453-508.
4. Suganuma, M., H. Fujiki, et al. (1990). "Calyculin A, an inhibitor of protein phosphatases, a potent tumor promoter on CD-1 mouse skin." Cancer Res 50(12): 3521-3525.
5. Helps, N. R., H. M. Barker, et al. (1995). "Protein phosphatase 1 interacts with p53BP2, a protein which binds to the tumour suppressor p53." FEBS Lett 377(3): 295-300.
6. Espanel, X. and M. Sudol (2001). "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains." J Biol Chem 276(17): 14514-14523.
7. Egloff, M. P., D. F. Johnson, et al. (1997). "Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1." EMBO J 16(8): 1876-1887.
8. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physio 1 Renal Physiol 294(3):F542-553.
9. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
10. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1." Proc Natl Acad Sci U S A 104(5):1631-1636.
11. Kanai, F., P. A. Marignani, et al. (2000). "TAZ:a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins." EMBO J 19(24):6778-6791.
12. Mitsuhashi, S., H. Shima, et al. (2003). "Usage of tautomycetin, a novel inhibitor of protein phosphatase 1 (PP1), reveals that PP1 is a positive regulator of Raf-1 in vivo." J Biol Chem 278(1):82-88.
13. Schlegelmilch, K., M. Mohseni, et al. (2011). "Yap1 Acts Downstream of alpha-Catenin to Control Epidermal Proliferation." Cell 144(5):782-795.
14. Hakuno, F., S. Kurihara, et al. (2007). "53BP2S, interacting with insulin receptor substrates, modulates insulin signaling." J Biol Chem 282(52):37747-37758.
15. Fernandez, L. A., P. A. Northcott, et al. (2009). "YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation." Genes Dev 23(23):2729-2741.
16. Vives, V., J. Su, et al. (2006). "ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth." Genes Dev 20(10):1262-1267.
17. Bergamaschi, D., Y. Samuels, et al. (2004). "ASPP1 and ASPP2:common activators of p53 family members." Mol Cell Biol 24(3):1341-1350.
18. Chen, Y., W. Liu, et al. (2003). "ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis." J Neurochem 85(3):801-809.
19. Vigneron, A. M., R. L. Ludwig, et al. (2010). "Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP." Genes Dev 24(21):2430-2439.
1. Chan, S. W., C. J. Lim, et al. (2008). "A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells." Cancer Res 68(8):2592-2598.
2. Hart, M., J. P. Concordet, et al. (1999). "The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell." Curr Biol 9(4): 207-210.
3. Tian, Y., R. Kolb, et al. (2007). "TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex." Mol Cell Biol 27(18):6383-6395.
4. Frescas, D. and M. Pagano (2008). "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP:tipping the scales of cancer." Nat Rev Cancer 8(6):438-449.
5. Kalousi, A., I. Mylonis, et al. (2010). "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1." J Cell Sci 123(Pt 17):2976-2986.
6. Behrend, L., D. M. Milne, et al. (2000). "IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects." Oncogene 19(47):5303-5313.
7. Rena, G., J. Bain, et al. (2004). "D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXOla." EMBO Rep 5(1):60-65.
8. Morin-Kensicki, E. M., B. N. Boone, et al. (2006). "Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65." Mol Cell Biol 26(1):77-87.
9. Sawada, A., H. Kiyonari, et al. (2008). "Redundant roles of Teadl and Tead2 in notochord development and the regulation of cell proliferation and survival." Mol Cell Biol 28(10):3177-3189.
10. Makita, R., Y. Uchijima, et al. (2008). "Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ." Am J Physiol Renal Physiol 294(3):F542-553.
11. Hossain, Z., S. M. Ali, et al. (2007). "Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtrl." Proc Natl Acad Sci U S A 104(5):1631-1636.
12. Zhao, B., X.Wei, et al. (2007). "Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control." Genes Dev 21(21):2747-2761.
13. Zhou, Z., Y.Hao, et al. (2011). "TAZ is a novel oncogene in non-small cell lung cancer." Oncogene.
14. de Cristofaro, T., T. Di Palma, et al. (2011). "TAZ/WWTR1 is overexpressed in papillary thyroid carcinoma." Eur J Cancer 47(6):926-933.
15. Overholtzer, M., J. Zhang, et al. (2006). "Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon." Proc Natl Acad Sci U S A 103(33):12405-12410.