Abstract
The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.
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References
Drebin JA, Stern DF, Link VC, Weinberg RA, Greene MI . Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 1984; 312: 545–548.
Yoneda T, Kumagai T, Nagatomo I, Furukawa M, Yamane H, Hoshino S et al. The extracellular domain of p185(c-neu) induces density-dependent inhibition of cell growth in malignant mesothelioma cells and reduces growth of mesothelioma in vivo. DNA Cell Biol 2006; 25: 530–540.
Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol 2009; 11: 1444–1450.
Urtasun R, Latasa MU, Demartis MI, Balzani S, Goni S, Garcia-Irigoyen O et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology 2011; 54: 2149–2158.
Zhao B, Li L, Lei Q, Guan KL . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010; 24: 862–874.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007; 21: 2747–2761.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007; 130: 1120–1133.
Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 2007; 17: 2054–2060.
Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M et al. Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J Biol Chem 1995; 270: 14733–14741.
Zhao B, Ye X, Yu J, Li L, Li W, Li S et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008; 22: 1962–1971.
Lai D, Ho KC, Hao Y, Yang X . Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 2011; 71: 2728–2738.
Tapon N, Harvey KF, Bell DW, Wahrer DC, Schiripo TA, Haber DA et al. Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 2002; 110: 467–478.
Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A . SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr Biol 2008; 18: 435–441.
Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 2006; 103: 12405–12410.
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol 2008; 28: 2426–2436.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125: 1253–1267.
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D et al. Expression of Yes-associated protein in common solid tumors. Hum Pathol 2008; 39: 1582–1589.
Lee KP, Lee JH, Kim TS, Kim TH, Park HD, Byun JS et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc Natl Acad Sci USA 2010; 107: 8248–8253.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 2011; 30: 2810–2822.
Hall CA, Wang R, Miao J, Oliva E, Shen X, Wheeler T et al. Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res 2010; 70: 8517–8525.
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X . Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 2010; 101: 1279–1285.
Zhou Z, Hao Y, Liu N, Raptis L, Tsao MS, Yang X . TAZ is a novel oncogene in non-small cell lung cancer. Oncogene 2011; 30: 2181–2186.
Fernandez LA, Squatrito M, Northcott P, Awan A, Holland EC, Taylor MD et al. Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 2011; Aug: 29.
Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 2009; 23: 2729–2741.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X . Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 2008; 283: 5496–5509.
Basu S, Totty NF, Irwin MS, Sudol M . Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell 2003; 11: 11–23.
Zhao B, Li L, Tumaneng K, Wang CY, Guan KL . A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 2010; 24: 72–85.
Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi G et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell 2008; 32: 803–814.
Wang W, Huang J, Chen J . Angiomotin-like proteins associate with and negatively regulate YAP1. J Biol Chem 2011; 286: 4364–4370.
Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev 2011; 25: 51–63.
Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W . Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem 2011; 286: 7018–7026.
Ogata M, Takada T, Mori Y, Uchida Y, Miki T, Okuyama A et al. Regulation of phosphorylation level and distribution of PTP36, a putative protein tyrosine phosphatase, by cell-substrate adhesion. J Biol Chem 1999; 274: 20717–20724.
Ogata M, Takada T, Mori Y, Oh-hora M, Uchida Y, Kosugi A et al. Effects of overexpression of PTP36, a putative protein tyrosine phosphatase, on cell adhesion, cell growth, and cytoskeletons in HeLa cells. J Biol Chem 1999; 274: 12905–12909.
Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y . The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin. Mol Biol Cell 2003; 14: 2520–2529.
Wadham C, Gamble JR, Vadas MA, Khew-Goodall Y . Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation. J Cell Sci 2000; 113 (Pt 17): 3117–3123.
Wyatt L, Wadham C, Crocker LA, Lardelli M, Khew-Goodall Y . The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development. J Cell Biol 2007; 178: 1223–1235.
Niedergethmann M, Alves F, Neff JK, Heidrich B, Aramin N, Li L et al. Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model. Br J Cancer 2007; 97: 1432–1440.
Laczmanska I, Sasiadek MM . Tyrosine phosphatases as a superfamily of tumor suppressors in colorectal cancer. Acta Biochim Pol 2011; 58: 467–470.
Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 2004; 304: 1164–1166.
Andersen JN, Sathyanarayanan S, Di Bacco A, Chi A, Zhang T, Chen AH et al. Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors. Sci Transl Med 2010; 2: 43ra55.
Barr AJ, Debreczeni JE, Eswaran J, Knapp S . Crystal structure of human protein tyrosine phosphatase 14 (PTPN14) at 1.65-A resolution. Proteins 2006; 63: 1132–1136.
Smith AL, Mitchell PJ, Shipley J, Gusterson BA, Rogers MV, Crompton MR . Pez: a novel human cDNA encoding protein tyrosine phosphatase- and ezrin-like domains. Biochem Biophys Res Commun 1995; 209: 959–965.
Chen HI, Einbond A, Kwak SJ, Linn H, Koepf E, Peterson S et al. Characterization of the WW domain of human yes-associated protein and its polyproline-containing ligands. J Biol Chem 1997; 272: 17070–17077.
Sudol M, Chen HI, Bougeret C, Einbond A, Bork P . Characterization of a novel protein-binding module–the WW domain. FEBS Lett 1995; 369: 67–71.
Chen HI, Sudol M . The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules. Proc Natl Acad Sci USA 1995; 92: 7819–7823.
Sudol M, Sliwa K, Russo T . Functions of WW domains in the nucleus. FEBS Lett 2001; 490: 190–195.
Berezov A, Cai Z, Freudenberg JA, Zhang H, Cheng X, Thompson T et al. Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin. Oncogene 2012; 31: 1938–1948.
Webb C, Upadhyay A, Giuntini F, Eggleston I, Furutani-Seiki M, Ishima R et al. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry 2011; 50: 3300–3309.
Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem 2001; 276: 15164–15173.
Komuro A, Nagai M, Navin NE, Sudol M . 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 2003; 278: 33334–33341.
Yagi R, Chen LF, Shigesada K, Murakami Y, Ito YA . WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 1999; 18: 2551–2562.
Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L et al. Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level. Exp Cell Res 2004; 294: 469–479.
Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 2009; 139: 757–769.
Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML . TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev 2001; 15 (): 1229–1241.
Zhao B, Kim J, Ye X, Lai ZC, Guan KL, Both TEA . D-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein. Cancer Res 2009; 69: 1089–1098.
Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W . TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J Biol Chem 2009; 284: 14347–14358.
Poernbacher I, Baumgartner R, Marada SK, Edwards K, Stocker H . Drosophila Pez Acts in Hippo Signaling to Restrict Intestinal Stem Cell Proliferation. Curr Biol 2012; 22: 389–396.
Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H . The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 2010; 18: 309–316.
Genevet A, Wehr MC, Brain R, Thompson BJ, Tapon N . Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev Cell 2010; 18: 300–308.
Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D . Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 2010; 18: 288–299.
Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M et al. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem 2010; 285: 39260–39270.
Carlucci A, Gedressi C, Lignitto L, Nezi L, Villa-Moruzzi E, Avvedimento EV et al. Protein-tyrosine phosphatase PTPD1 regulates focal adhesion kinase autophosphorylation and cell migration. J Biol Chem 2008; 283: 10919–10929.
Wu ZZ, Lu HP, Chao CC . Identification and functional analysis of genes which confer resistance to cisplatin in tumor cells. Biochem Pharmacol 2010; 80: 262–276.
Cao X, Pfaff SL, Gage FH . YAP regulates neural progenitor cell number via the TEA domain transcription factor. Genes Dev 2008; 22: 3320–3334.
Acknowledgements
This work has been supported by funds from the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute of the Cedars-Sinai Medical Center (QW), the Donna and Jesse Garber Award for Cancer Research (QW), R01CA089481and R01 CA055306 from the National Cancer Institute (MIG), the Breast Cancer Research Foundation, and the Abramson Family Cancer Research Institute at the University of Pennsylvania (MIG).We thank these investigators for providing plasmids Masato Ogata (murine PTPN14/PEZ), Joan Brugge (YAP), Kunliang Guan (Gal4-TEAD4) and Marius Sudol (LATS1). We thank Dr Chao-Xing Yuan for performing proteomics analysis at the proteomics core facility at the University of Pennsylvania. The Proteomics Core was supported by grant P30CA016520 (Abramson Cancer Center) and by grant ES013508-04 (CEET). We also thank the members of the Women’s Cancer Program (Cedars-Sinai) and the Greene laboratory (UPenn) for helpful discussion.
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Huang, JM., Nagatomo, I., Suzuki, E. et al. YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32, 2220–2229 (2013). https://doi.org/10.1038/onc.2012.231
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DOI: https://doi.org/10.1038/onc.2012.231
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