Letter | Published:

YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29

Nature Cell Biology volume 14, pages 13221329 (2012) | Download Citation

Abstract

Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

  2. 2.

    et al. The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).

  3. 3.

    et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010).

  4. 4.

    et al. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 17, 6649–6659 (1998).

  5. 5.

    et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186 (1994).

  6. 6.

    , , & Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat. Cell Biol. 1, 500–506 (1999).

  7. 7.

    et al. Inactivation of YAP oncoprotein by the Hippo pathway is involvedin cell contact inhibition and tissue growth control. Gen. Dev. 21, 2747–2761 (2007).

  8. 8.

    et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat. Cell Biol. 8, 27–36 (2006).

  9. 9.

    , , , & The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122, 421–434 (2005).

  10. 10.

    et al. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675–685 (2005).

  11. 11.

    , , & 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 (2003).

  12. 12.

    , , , & Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem. 283, 5496–5509 (2008).

  13. 13.

    , & Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. Cancer Res. 68, 2789–2794 (2008).

  14. 14.

    et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076–2086 (2005).

  15. 15.

    et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

  16. 16.

    , , , & Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev. Biol. 367, 187–196 (2012).

  17. 17.

    , & Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila. Dev. Biol. 369, 115–123 (2012).

  18. 18.

    et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054–2060 (2007).

  19. 19.

    et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat. Cell Biol. 11, 1444–1450 (2009).

  20. 20.

    et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012).

  21. 21.

    , , , & Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Gen. Dev. 26, 2138–2143 (2012).

  22. 22.

    et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).

  23. 23.

    , , , & A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551–2562 (1999).

  24. 24.

    , , & Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell. Biol. 20, 5010–5018 (2000).

  25. 25.

    , & Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379 (2010).

  26. 26.

    & The Hippo pathway regulates the bantammicroRNA to control cell proliferation and apoptosis in Drosophila. Cell 126, 767–774 (2006).

  27. 27.

    , , , & The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr. Biol. 16, 1895–1904 (2006).

  28. 28.

    , , & miR-29b regulates migration of human breast cancer cells. Mol. Cell. Biochem. 352, 197–207 (2011).

  29. 29.

    et al. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS one 6, e19518 (2011).

  30. 30.

    et al. TEAD mediates YAP-dependent gene induction and growth control. Gen. Dev. 22, 1962–1971 (2008).

  31. 31.

    , & YAP regulates neural progenitor cell number via the TEA domain transcription factor. Gen. Dev. 22, 3320–3334 (2008).

  32. 32.

    et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

  33. 33.

    et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 7, e1000121 (2009).

Download references

Acknowledgements

We thank F. Furnari and M. Wicha for reagents. We thank J. Zhao for technical help, and J. Kim and B. Zhao for thoughtful discussions. The deep-sequencing service was provided by LC Sciences. K.T. was supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology. K-L.G. is supported by grants from the NIH.

Author information

Affiliations

  1. Department of Pharmacology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA

    • Karen Tumaneng
    • , Ryan C. Russell
    •  & Kun-Liang Guan
  2. Biomedical Sciences Graduate Program, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA

    • Karen Tumaneng
    • , Harihar Basnet
    •  & Navin Mahadevan
  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Karin Schlegelmilch
    • , Dean Yimlamai
    •  & Fernando D. Camargo
  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Julien Fitamant
    •  & Nabeel Bardeesy
  5. Institute for Chemistry/Biochemistry, FU Berlin, Berlin 14195, Germany

    • Karin Schlegelmilch

Authors

  1. Search for Karen Tumaneng in:

  2. Search for Karin Schlegelmilch in:

  3. Search for Ryan C. Russell in:

  4. Search for Dean Yimlamai in:

  5. Search for Harihar Basnet in:

  6. Search for Navin Mahadevan in:

  7. Search for Julien Fitamant in:

  8. Search for Nabeel Bardeesy in:

  9. Search for Fernando D. Camargo in:

  10. Search for Kun-Liang Guan in:

Contributions

K.T. performed the experiments. K.S. conducted the LY294002 animal experiment. K.T. and R.C.R. performed fluorescent immunohistochemistry staining experiments. D.Y. prepared mouse tissue slides for immunohistochemistry experiments. K.T. and H.B. performed luciferase and ChIP assays. K.T. and N.M. conducted flow cytometry experiments. J.F. and N.B. provided the Mst1/2-knockout mouse liver tissues. K.S. and F.D.C. designed the LY294002 animal experiment. K.T. and K-L.G. designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kun-Liang Guan.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncb2615

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing