Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner

Oncogene volume 34, pages 4190–4198 (2015)Cite this article

Subjects

Abstract

The polyomavirus middle T antigen (PyMT) is an oncogene that activates the non-receptor tyrosine kinase, c-Src, and physically interacts with Taz (WWTR1). Taz is a pro-oncogenic transcription coactivator of the Tead transcription factors. The Hippo tumor suppressor pathway activates the kinase Lats, which phosphorylates Taz, leading to its nuclear exclusion and blunting Tead coactivation. We found that Taz was required for transformation by PyMT, but counter-intuitively, Taz was exclusively cytoplasmic in the presence of PyMT. We demonstrate that in the presence of PyMT, wild-type Taz was phosphorylated by Lats, in a Src-dependent manner. Consistently, a Lats refractory Taz mutant did not undergo cytoplasmic retention by PyMT. We show that Yap, the Taz paralog, and Shp2 phosphatase were nuclear excluded as well. Our findings describe a noncanonical activation of Lats, and an unprecedented Tead-independent role for Taz and Yap in viral-mediated oncogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. O'Shea CC . DNA tumor viruses—the spies who lyse us. Curr Opin Genet Dev 2005; 15: 18–26.

    Article  CAS  PubMed  Google Scholar 

  2. Helt A-M, Galloway DA . Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis 2003; 24: 159–169.

    Article  CAS  PubMed  Google Scholar 

  3. Fluck MM, Schaffhausen BS . Lessons in signaling and tumorigenesis from polyomavirus middle T antigen. Microbiol Mol Biol Rev 2009; 73: 542–563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Treisman R, Novak U, Favaloro J, Kamen R . Transformation of rat cells by an altered polyoma virus genome expressing only the middle-T protein. Nature 1981; 292: 595–600.

    Article  CAS  PubMed  Google Scholar 

  5. Guy CT, Cardiff RD, Muller WJ . Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 1992; 12: 954–961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gottlieb KA, Villarreal LP . Natural biology of polyomavirus middle T antigen. Microbiol Mol Biol Rev 2001; 65: 288–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Courtneidge SA, Smith AE . The complex of polyoma virus middle-T antigen and pp60c-src. EMBO J 1984; 3: 585–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ . Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev 1994; 8: 23–32.

    Article  CAS  PubMed  Google Scholar 

  9. Harvey R, Oostra BA, Belsham GJ, Gillett P, Smith AE . An antibody to a synthetic peptide recognizes polyomavirus middle-T antigen and reveals multiple in vitro tyrosine phosphorylation sites. Mol Cell Biol 1984; 4: 1334–1342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kamps MP, Buss JE, Sefton BM . Mutation of NH2-terminal glycine of p60src prevents both myristoylation and morphological transformation. Proc Natl Acad Sci USA 1985; 82: 4625–4628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schaffhausen B, Benjamin TL . Comparison of phosphorylation of two polyoma virus middle T antigens in vivo and in vitro. J Virol 1981; 40: 184–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao B, Wei X, Li W . Inactivation of Yap oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007; 21: 2747–2761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng Q, Hong W . The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 2008; 13: 188–192.

    Article  CAS  PubMed  Google Scholar 

  14. Hao Y, Chun A, Cheung K, Rashidi B, Yang X . Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem 2007; 283: 5496–5509.

    Article  PubMed  Google Scholar 

  15. Liu C-Y, Zha Z-Y, Zhou X, Zhang H, Huang W, Zhao D et al. The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCFβ-TrCP E3 ligase. J Biol Chem 2010; 285: 37159–37169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mahoney WMJ, Hong J-H, Yaffe MB, Farrance IKG . The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. Biochem J 2005; 388: 217–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lei Q-Y, Zhang H, Zhao B, Zha Z-Y, Bai F, Pei X-H et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Molec Cell Biol 2008; 28: 2426–2436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M et al. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J 2000; 19: 6778–6791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Halder G, Johnson RL . Hippo signaling: growth control and beyond. Development 2011; 138: 9–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tian Y, Li D, Dahl J, You J, Benjamin T . Identification of TAZ as a Binding Partner of the Polyomavirus T Antigens. J Virol 2004; 77: 12657–12664.

    Article  Google Scholar 

  24. Glenn GM, Eckhart W . Amino-terminal regions of polyomavirus middle T antigen are required for interactions with protein phosphatase 2A. J Virol 1995; 69: 3729–3736.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cook DN, Hassell JA . The amino terminus of polyomavirus middle T antigen is required for transformation. J Virol 1990; 64: 1879–1887.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Campbell KS, Auger KR, Hemmings BA, Roberts TM, Pallas DC . Identification of regions in polyomavirus middle T and small t antigens important for association with protein phosphatase 2A. J Virol 1995; 69: 3721–3728.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tsutsumi R, Masoudi M, Takahashi A, Fujii Y, Hayashi T, Kikuchi I et al. YAP and TAZ, Hippo signaling targets, act as a rheostat for nuclear SHP2 function. Dev Cell 2013; 26: 658–665.

    Article  CAS  PubMed  Google Scholar 

  28. Yang Y, Jiang B, Huo Y, Primo L, Dahl JS, Benjamin TL et al. Shp2 suppresses PyMT-induced transformation in mouse fibroblasts by inhibiting Stat3 activity. Virology 2011; 409: 204–210.

    Article  CAS  PubMed  Google Scholar 

  29. Ota M, Sasaki H . Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. Development 2008; 135: 4059–4069.

    Article  CAS  PubMed  Google Scholar 

  30. Zhao B, Kim J, Ye X, Lai ZC, Guan KL . Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein. Cancer Res 2009; 69: 1089–1098.

    Article  CAS  PubMed  Google Scholar 

  31. Schaffhausen BS, Roberts TM . Lessons from polyoma middle T antigen on signaling and transformation: A DNA tumor virus contribution to the war on cancer. Virology 2009; 384: 304–316.

    Article  CAS  PubMed  Google Scholar 

  32. Dilworth SM . Polyoma virus middle T antigen: meddler or mimic? Trends Microbiol 1995; 3: 31–35.

    Article  CAS  PubMed  Google Scholar 

  33. Raptis L, Lamfrom H, Benjamin TL . Regulation of cellular phenotype and expression of polyomavirus middle T antigen in rat fibroblasts. Mol Cell Biol 1985; 5: 2476–2486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Primo L, Roca C, Ferrandi C, Lanfrancone L, Bussolino F . Human endothelial cells expressing polyoma middle T induce tumors. Oncogene 2000; 19: 3632–3641.

    Article  CAS  PubMed  Google Scholar 

  36. Williams RL, Risau W, Zerwes HG, Drexler H, Aguzzi A, Wagner EF . Endothelioma cells expressing the polyoma middle T oncogene induce hemangiomas by host cell recruitment. Cell 1989; 57: 1053–1063.

    Article  CAS  PubMed  Google Scholar 

  37. Grazia Lampugnani M, Zanetti A, Corada M, Takahashi T, Balconi G, Breviario F et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol 2003; 161: 793–804.

    Article  PubMed  Google Scholar 

  38. Levy D, Adamovich Y, Reuven N, Shaul Y . The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell Death Differ 2007; 14: 743–751.

    Article  CAS  PubMed  Google Scholar 

  39. Morgenstern JP, Land H . Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 1990; 18: 3587–3596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carey MF, Peterson CL, Smale ST . Dignam and Roeder nuclear extract preparation. Cold Spring Harb Protoc 2009; 2009: pdb prot5330.

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs R Bassel-Duby for pCDNA3-Flag-mTaz, pCDNA-myc-mTaz and pCDNA-myc-mTazWA plasmids; M Sudol for pCMV-Yap1 plasmid; J Zhang for pBP-GFP-hTaz-4SA plasmid; H Sasaki for pBS-8xGTIIC-Luc (8xGTIIC) Tead reporter plasmid; A Elson for mSrc sequence; M Oren for Myc-tagged human Lats2 constructs; and XJ Yang for HA-tagged Lats2, Lats-KM, Mst1 and WW45 constructs; B Neel for Shp2 C459S and E76K constructs. We thank Dr Z Porat for his help with ImageStream technology. This work was supported by grants from the Israel Science Foundation (grant No. 551/11), Israel Cancer Research Fund and from the Minerva Foundation with funding from the Federal German Ministry for Education and Research.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    M Shanzer, I Ricardo-Lax, R Keshet, N Reuven & Y Shaul

Authors
  1. M Shanzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Ricardo-Lax
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Keshet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Reuven
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Shaul
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Shaul.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shanzer, M., Ricardo-Lax, I., Keshet, R. et al. The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner. Oncogene 34, 4190–4198 (2015). https://doi.org/10.1038/onc.2014.347

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.347

This article is cited by

Search

Advanced search

Quick links