Article | Published:

AMPK modulates Hippo pathway activity to regulate energy homeostasis

Nature Cell Biology volume 17, pages 490499 (2015) | Download Citation

Abstract

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

  2. 2.

    , , & The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 24, 862–874 (2010).

  3. 3.

    & Hippo signaling: growth control and beyond. Development 138, 9–22 (2011).

  4. 4.

    , , , & A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβTRCP. Genes Dev. 24, 72–85 (2010).

  5. 5.

    et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25, 166–180 (2014).

  6. 6.

    et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res. 24, 331–343 (2014).

  7. 7.

    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).

  8. 8.

    et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

  9. 9.

    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).

  10. 10.

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

  11. 11.

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

  12. 12.

    , & The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 15, 642–656 (2014).

  13. 13.

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

  14. 14.

    et al. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54–68 (2012).

  15. 15.

    , & Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012).

  16. 16.

    et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

  17. 17.

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

  18. 18.

    & Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009).

  19. 19.

    , & Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

  20. 20.

    et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

  21. 21.

    , , , & Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J. Biol. Chem. 273, 35347–35354 (1998).

  22. 22.

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

  23. 23.

    et al. ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA. Biochem. Biophys. Res. Commun. 368, 162–167 (2008).

  24. 24.

    et al. Akt and RhoA activation in response to high glucose require caveolin-1 phosphorylation in mesangial cells. Am. J. Physiol. Renal Physiol. 306, F1308–F1317 (2014).

  25. 25.

    , , , & High glucose-induced RhoA activation requires caveolae and PKCbeta1-mediated ROS generation. Am. J. Physiol. Renal Physiol. 302, F159–F172 (2012).

  26. 26.

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

  27. 27.

    , , & Causes and consequences of tumour acidity and implications for treatment. Mol. Med. Today 6, 15–19 (2000).

  28. 28.

    , & Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc. Natl Acad. Sci. USA 108, 2270–2275 (2011).

  29. 29.

    et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem. Biophys. Res. Commun. 170, 223–230 (1990).

  30. 30.

    , , & Expression of glucose transporters in head-and-neck tumors. Int. J. Cancer 56, 622–629 (1994).

  31. 31.

    , & Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Brain Res. Mol. Brain Res. 27, 51–57 (1994).

  32. 32.

    , , , & Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer 80, 1046–1051 (1997).

  33. 33.

    et al. GLUT1 and GLUT3 as potential prognostic markers for oral squamous cell carcinoma. Molecules 15, 2374–2387 (2010).

  34. 34.

    & CAV1/caveolin 1 enhances aerobic glycolysis in colon cancer cells via activation of SLC2A3/GLUT3 transcription. Autophagy 8, 1684–1685 (2012).

  35. 35.

    et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, (2015).

  36. 36.

    et al. Energy stress regulates Hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep. 9, 495–503 (2014).

  37. 37.

    , , & Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal. Chem. 68, 850–858 (1996).

  38. 38.

    & Proteomics: the move to mixtures. J. Mass Spectrom. 36, 1083–1091 (2001).

  39. 39.

    , & An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J. Am. Soc. Mass Spectrom. 5, 976–989 (1994).

  40. 40.

    , , , & A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. 24, 1285–1292 (2006).

Download references

Acknowledgements

We thank all of our colleagues in the Chen laboratory for insightful discussion and technical assistance, especially J. Yuan, G. Ghosal and B. C. Nair. We also thank J-I. Park, L. Ma, Y. Sun, J. Zhang, A. Lin and H. Lee for reagents, insightful suggestions and comments on this work. We thank F-X. Yu (University of California, San Diego) for technical help. We thank the shRNA-ORFeome Core Facility at MD Anderson Cancer Center for the ORFs and shRNAs. We thank B. Viollet for providing AMPK wild-type and knockout MEFs. We thank K. Hale for proof-reading the manuscript. We thank R. Tomaino for assistance with the mass spectrometry analysis. This work was supported in part by the US Department of Defense Era of Hope research scholar award to J.C. (W81XWH-09-1-0409 and W81XWH-05-1-0470). This work was partly supported by the U.S. National Cancer Institute through the MD Anderson Cancer Center Support Grant (CA016672).

Author information

Affiliations

  1. Department of Experimental Radiation Oncology, 1515 Holcombe Boulevard Houston, Texas 77030, USA

    • Wenqi Wang
    • , Zhen-Dong Xiao
    • , Xu Li
    • , Kathryn E. Aziz
    • , Boyi Gan
    •  & Junjie Chen
  2. Cancer Biology Program, The University of Texas Graduate School of Biomedical Science, 1515 Holcombe Boulevard Houston, Texas 77030, USA

    • Boyi Gan
    • , Randy L. Johnson
    •  & Junjie Chen
  3. Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Houston, Texas 77030, USA

    • Randy L. Johnson

Authors

  1. Search for Wenqi Wang in:

  2. Search for Zhen-Dong Xiao in:

  3. Search for Xu Li in:

  4. Search for Kathryn E. Aziz in:

  5. Search for Boyi Gan in:

  6. Search for Randy L. Johnson in:

  7. Search for Junjie Chen in:

Contributions

W.W. performed all of the experiments with assistance from Z-D.X., X.L., K.E.A., B.G., R.L.J. and J.C. W.W. and J.C. designed the experiments. J.C. supervised the study. W.W. and J.C. wrote the manuscript. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Junjie Chen.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

Excel files

  1. 1.

    Supplementary Table 1

    Supplementary Information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncb3113

Further reading