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.

  • Opinion
  • Published:

A two-way street: reciprocal regulation of metabolism and signalling

Nature Reviews Molecular Cell Biology volume 13, pages 270–276 (2012)Cite this article

Subjects

Abstract

It is becoming increasingly clear that cellular signalling and metabolism are not just separate entities but rather are tightly linked. Although nutrient metabolism is known to be regulated by signal transduction, an emerging paradigm is that signalling and transcriptional networks can be modulated by nutrient-sensitive protein modifications, such as acetylation and glycosylation, which depend on the availability of acetyl-CoA and sugar donors such as UDP-N-acetylglucosamine (UDP-GlcNAc), respectively. The integration of metabolic and signalling cues allows cells to modulate activities such as metabolism, cell survival and proliferation according to their intracellular metabolic resources.

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: Metabolic control of acetyl-CoA production.
Figure 2: A positive feedback loop linking metabolism, glycosylation and growth factor signalling.
Figure 3: Acetylation and glycosylation indicate nutrient sufficiency and promote growth.

Similar content being viewed by others

References

  1. Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T-cell response. Nature Rev. Immunol. 5, 844–852 (2005).

    CAS  Google Scholar 

  2. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190–202 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chang, L., Chiang, S. H. & Saltiel, A. R. Insulin signaling and the regulation of glucose transport. Mol. Med. 10, 65–71 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Herman, M. A. & Kahn, B. B. Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J. Clin. Invest. 116, 1767–1775 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).

    CAS  PubMed  Google Scholar 

  6. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011).

    CAS  Google Scholar 

  7. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biol. 13, 1016–1023 (2011).

    CAS  PubMed  Google Scholar 

  9. Hardie, D. G. AMPK and autophagy get connected. EMBO J. 30, 634–635 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Howell, J. J. & Manning, B. D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab. 22, 94–102 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).

    CAS  Google Scholar 

  12. Metallo, C. M. & Vander Heiden, M. G. Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev. 24, 2717–2722 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wellen, K. E. & Thompson, C. B. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol. Cell 40, 323–332 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Guan, K. L. & Xiong, Y. Regulation of intermediary metabolism by protein acetylation. Trends Biochem. Sci. 36, 108–116 (2011).

    CAS  Google Scholar 

  15. Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schwer, B. & Verdin, E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 7, 104–112 (2008).

    CAS  PubMed  Google Scholar 

  17. Easlon, E., Tsang, F., Skinner, C., Wang, C. & Lin, S. J. The malate–aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast. Genes Dev. 22, 931–944 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lin, S. J., Ford, E., Haigis, M., Liszt, G. & Guarente, L. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 18, 12–16 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    PubMed  PubMed Central  Google Scholar 

  20. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 7 Mar 2011 (doi:10.1038/nrm3293).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Morrish, F. et al. Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry. J. Biol. Chem. 285, 36267–36274 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tu, B. P. et al. Cyclic changes in metabolic state during the life of a yeast cell. Proc. Natl Acad. Sci. USA 104, 16886–16891 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wolfe, A. J. The acetate switch. Microbiol. Mol. Biol. Rev. 69, 12–50 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Takahashi, H., McCaffery, J. M., Irizarry, R. A. & Boeke, J. D. Nucleocytosolic acetyl-coenzyme A synthetase is required for histone acetylation and global transcription. Mol. Cell 23, 207–217 (2006).

    CAS  PubMed  Google Scholar 

  26. Albaugh, B. N., Arnold, K. M. & Denu, J. M. KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism. Chembiochem 12, 290–298 (2011).

    CAS  PubMed  Google Scholar 

  27. Spencer, A. F. & Lowenstein, J. M. The supply of precursors for the synthesis of fatty acids. J. Biol. Chem. 237, 3640–3648 (1962).

    CAS  PubMed  Google Scholar 

  28. Hardwick, D. C. The fate of acetyl groups derived from glucose in the isolated perfused goat udder. Biochem. J. 99, 228–231 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bartley, J., Abraham, S. & Chaikoff, I. L. Concerning the form in which acetyl units produced in mitochondria are transferred to the site of de novo fatty acid synthesis in the cell. Biochem. Biophys. Res. Commun. 19, 770–776 (1965).

    CAS  PubMed  Google Scholar 

  30. Pereira, C. V., Lebiedzinsk, M., Wieckowski, M. R. & Oliveira, P. J. Regulation and protection of mitochondrial physiology by sirtuins. Mitochondrion 12, 66–76 (2011).

    PubMed  Google Scholar 

  31. Verdin, E., Hirschey, M. D., Finley, L. W. & Haigis, M. C. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 35, 669–675 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Deberardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

    CAS  PubMed  Google Scholar 

  35. Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006).

    CAS  PubMed  Google Scholar 

  36. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Knosp, O., Talasz, H. & Puschendorf, B. Histone acetylation and histone synthesis in mouse fibroblasts during quiescence and restimulation into S-phase. Mol. Cell. Biochem. 101, 51–58 (1991).

    CAS  PubMed  Google Scholar 

  38. Migita, T. et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 68, 8547–8554 (2008).

    CAS  PubMed  Google Scholar 

  39. Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C. B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).

    CAS  PubMed  Google Scholar 

  40. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    CAS  PubMed  Google Scholar 

  41. Knoepfler, P. S. et al. Myc influences global chromatin structure. EMBO J. 25, 2723–2734 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dang, C. V. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 70, 859–862 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cai, L., Sutter, B. M., Li, B. & Tu, B. P. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol. Cell 42, 426–437 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Yi, C. H. et al. Metabolic regulation of protein N-α-acetylation of Bcl-xL promotes cell survival. Cell 146, 607–620 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kelly, P. N., Grabow, S., Delbridge, A. R., Strasser, A. & Adams, J. M. Endogenous Bcl-xL is essential for Myc-driven lymphomagenesis in mice. Blood 118, 6380–6386 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lv, L. et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin, Y. Y. et al. Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell 136, 1073–1084 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jiang, W. et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol. Cell 43, 33–44 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    CAS  PubMed  Google Scholar 

  51. Mazurek, S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol. 43, 969–980 (2011).

    CAS  PubMed  Google Scholar 

  52. Dominy, J. E. Jr, Lee, Y., Gerhart-Hines, Z. & Puigserver, P. Nutrient-dependent regulation of PGC-1α's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim. Biophys. Acta 1804, 1676–1683 (2010).

    CAS  PubMed  Google Scholar 

  53. Jeninga, E. H., Schoonjans, K. & Auwerx, J. Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29, 4617–4624 (2010).

    CAS  PubMed  Google Scholar 

  54. Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000).

    CAS  PubMed  Google Scholar 

  55. Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002).

    CAS  PubMed  Google Scholar 

  56. Sale, E. M., Hodgkinson, C. P., Jones, N. P. & Sale, G. J. A new strategy for studying protein kinase B and its three isoforms. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. Biochemistry 45, 213–223 (2006).

    CAS  PubMed  Google Scholar 

  57. Hanover, J. A., Krause, M. W. & Love, D. C. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim. Biophys. Acta 1800, 80–95 (2010).

    CAS  PubMed  Google Scholar 

  58. Slawson, C., Copeland, R. J. & Hart, G. W. O-GlcNAc signaling: a metabolic link between diabetes and cancer? Trends Biochem. Sci. 35, 547–555 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Marshall, S. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci. STKE 2006, re7 (2006).

    PubMed  Google Scholar 

  60. Marshall, S., Bacote, V. & Traxinger, R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266, 4706–4712 (1991).

    CAS  PubMed  Google Scholar 

  61. Dennis, J. W., Nabi, I. R. & Demetriou, M. Metabolism, cell surface organization, and disease. Cell 139, 1229–1241 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. Love, D. C. & Hanover, J. A. The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci. STKE 2005, re13 (2005).

    PubMed  Google Scholar 

  63. Wellen, K. E. et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 24, 2784–2799 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 (1985).

    CAS  PubMed  Google Scholar 

  65. Boscher, C., Dennis, J. W. & Nabi, I. R. Glycosylation, galectins and cellular signaling. Curr. Opin. Cell Biol. 23, 383–392 (2011).

    CAS  PubMed  Google Scholar 

  66. Lau, K. S. et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123–134 (2007).

    CAS  PubMed  Google Scholar 

  67. Partridge, E. A. et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120–124 (2004).

    CAS  PubMed  Google Scholar 

  68. Granovsky, M. et al. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nature Med. 6, 306–312 (2000).

    CAS  PubMed  Google Scholar 

  69. Cheung, P. & Dennis, J. W. Mgat5 and Pten interact to regulate cell growth and polarity. Glycobiology 17, 767–773 (2007).

    CAS  PubMed  Google Scholar 

  70. Ohtsubo, K., Chen, M. Z., Olefsky, J. M. & Marth, J. D. Pathway to diabetes through attenuation of pancreatic β-cell glycosylation and glucose transport. Nature Med. 17, 1067–1075 (2011).

    CAS  PubMed  Google Scholar 

  71. Ohtsubo, K. et al. Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123, 1307–1321 (2005).

    CAS  PubMed  Google Scholar 

  72. Fang, M. et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143, 711–724 (2010).

    CAS  PubMed  Google Scholar 

  73. Slawson, C. et al. Perturbations in O-linked β-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J. Biol. Chem. 280, 32944–32956 (2005).

    CAS  PubMed  Google Scholar 

  74. Caldwell, S. A. et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29, 2831–2842 (2010).

    CAS  PubMed  Google Scholar 

  75. Boehmelt, G. et al. Decreased UDP-GlcNAc levels abrogate proliferation control in EMeg32-deficient cells. EMBO J. 19, 5092–5104 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang, Z. et al. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci. Signal. 3, ra2 (2010).

    PubMed  PubMed Central  Google Scholar 

  77. Asher, G. & Schibler, U. Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab. 13, 125–137 (2011).

    CAS  PubMed  Google Scholar 

  78. Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism control by the circadian clock and vice versa. Nature Struct. Mol. Biol. 16, 462–467 (2009).

    CAS  Google Scholar 

  79. Le, A. et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 15, 110–121 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yoo, H., Antoniewicz, M. R., Stephanopoulos, G. & Kelleher, J. K. Quantifying reductive carboxylation flux of glutamine to lipid in a brown adipocyte cell line. J. Biol. Chem. 283, 20621–20627 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011).

    PubMed  PubMed Central  Google Scholar 

  82. Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mullen A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2011).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

C.B.T. is supported by grants from the US National Cancer Institute (NCI), the US National Institutes of Health (NIH) and Stand Up To Cancer. The authors are grateful to X. Yang and J. Dennis for critical reading of and feedback on the manuscript.

Author information

Authors and Affiliations

  1. Kathryn E. Wellen is at the Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,

    Kathryn E. Wellen

  2. Craig B. Thompson is at the Memorial Sloan-Kettering Cancer Center, Cancer Biology and Genetics Program, New York, New York 10065, USA.,

    Craig B. Thompson

Authors
  1. Kathryn E. Wellen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig B. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kathryn E. Wellen or Craig B. Thompson.

Ethics declarations

Competing interests

Craig B. Thompson is a founder of Agios Pharmaceuticals.

Kathryn E. Wellen declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Craig B. Thompson's homepage

Kathryn E. Wellen's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wellen, K., Thompson, C. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 13, 270–276 (2012). https://doi.org/10.1038/nrm3305

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3305

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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