Energy-dependent regulation of cell structure by AMP-activated protein kinase (original) (raw)

Nature volume 447, pages 1017–1020 (2007)Cite this article

Abstract

AMP-activated protein kinase (AMPK, also known as SNF1A) has been primarily studied as a metabolic regulator that is activated in response to energy deprivation1. Although there is relatively ample information on the biochemical characteristics of AMPK, not enough data exist on the in vivo function of the kinase. Here, using the Drosophila model system, we generated the first animal model with no AMPK activity and discovered physiological functions of the kinase. Surprisingly, _AMPK_-null mutants were lethal with severe abnormalities in cell polarity and mitosis, similar to those of _lkb1_-null mutants. Constitutive activation of AMPK restored many of the phenotypes of _lkb1_-null mutants, suggesting that AMPK mediates the polarity- and mitosis-controlling functions of the LKB1 serine/threonine kinase. Interestingly, the regulatory site of non-muscle myosin regulatory light chain (MRLC; also known as MLC2)2,3 was directly phosphorylated by AMPK. Moreover, the phosphomimetic mutant of MRLC3 rescued the _AMPK_-null defects in cell polarity and mitosis, suggesting MRLC is a critical downstream target of AMPK. Furthermore, the activation of AMPK by energy deprivation was sufficient to cause dramatic changes in cell shape, inducing complete polarization and brush border formation in the human LS174T cell line, through the phosphorylation of MRLC. Taken together, our results demonstrate that AMPK has highly conserved roles across metazoan species not only in the control of metabolism, but also in the regulation of cellular structures.

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Acknowledgements

We would like to thank A. Wodarz, K. L. Guan, R. Fehon, C. Sunkel, R. Saint, H. Piwnica-Worms, D. St Johnston, C. Q. Doe, R. T. Moon, M. Montminy, L. Alphey and H. Clever, as well as the Bloomington Stock Center, Developmental Studies Hybridoma Bank and Drosophila Genomics Research Center, for kindly providing materials. We also thank the Korea Basic Science Institute for electron microscopy analyses and the Korean Cell Line Bank for LS174T cell stock. This research was supported by a National Creative Research Initiatives grant from the Korean Ministry of Science and Technology/KOSEF.

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Author notes

  1. Jun Hee Lee, Hyongjong Koh and Myungjin Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. National Creative Research Initiatives Center for Cell Growth Regulation, and,,
    Jun Hee Lee, Hyongjong Koh, Myungjin Kim, Yongsung Kim, Soo Young Lee & Jongkyeong Chung
  2. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-Dong, Yusong-Gu, Taejon 305-701, Korea,
    Jun Hee Lee, Hyongjong Koh, Myungjin Kim, Yongsung Kim, Soo Young Lee, Jaeseob Kim & Jongkyeong Chung
  3. Centre National de la Recherche Scientifique, Centre de Génétique Moléculaire, Avenue de la Terrasse, 91198 Gif sur Yvette, France,
    Roger E. Karess
  4. Division of Electron Microscopic Research, Korea Basic Science Institute, 52 Eoeun-Dong, Yusong-Gu, Taejon 305-333, Korea,
    Sang-Hee Lee
  5. Department of Internal Medicine, and,
    Minho Shong
  6. Department of Pathology, Chungnam National University School of Medicine, 640 Daesa-Dong, Chung-Gu, Taejon 301-721, Korea,
    Jin-Man Kim
  7. GenExel, 373-1 Kusong-Dong, Yusong-Gu, Taejon 305-701, Korea,
    Jaeseob Kim

Authors

  1. Jun Hee Lee
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  2. Hyongjong Koh
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  3. Myungjin Kim
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  4. Yongsung Kim
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  5. Soo Young Lee
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  6. Roger E. Karess
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  7. Sang-Hee Lee
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  8. Minho Shong
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  9. Jin-Man Kim
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  10. Jaeseob Kim
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  11. Jongkyeong Chung
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Correspondence toJongkyeong Chung.

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J.C. and J.K. have stocks in GenExel Incorporation.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-16 with Legends and additional references. (PDF 2787 kb)

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Lee, J., Koh, H., Kim, M. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase.Nature 447, 1017–1020 (2007). https://doi.org/10.1038/nature05828

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