The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

Baena-Gonzalez, E., Rolland, F., Thevelein, J. M. & Sheen, J. A central integrator of transcription networks in plant stress and energy signalling. Nature 448, 938–942 (2007).

Hedbacker, K. & Carlson, M. SNF1/AMPK pathways in yeast. Front Biosci. 13, 2408–2420 (2008).

Bokko, P. B. et al. Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling. Mol. Biol. Cell 18, 1874–1886 (2007).

Narbonne, P. & Roy, R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457, 210–214 (2009).

Johnson, E. C. et al. Altered metabolism and persistent starvation behaviors caused by reduced AMPK function in Drosophila. PLoS One 5, e12799 (2010).

Thelander, M., Olsson, T. & Ronne, H. Snf1-related protein kinase 1 is needed for growth in a normal day-night light cycle. EMBO J. 23, 1900–1910 (2004).

Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol. 8, 774–785 (2007).

Hardie, D. G., Carling, D. & Gamblin, S. J. AMP-activated protein kinase: also regulated by ADP? Trends Biochem. Sci. http://dx.doi.org/10.1016/j.tibs.2011.06.004 (2011).

Xiao, B. et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233 (2011).

Oakhill, J. S. et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435 (2011).

Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

Shackelford, D. B. & Shaw, R. J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).

Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).

Hurley, R. L. et al. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060–29066 (2005).

Woods, A. et al. C(Ca2+)/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005).

Fogarty, S. et al. Calmodulin-dependent protein kinase kinase-β activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem. J. 426, 109–118 (2010).

Xie, M. et al. A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc. Natl Acad. Sci. USA 103, 17378–17383 (2006).

Herrero-Martin, G. et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28, 677–685 (2009).

Salt, I. et al. AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the α2 isoform. Biochem. J. 334, 177–187 (1998).

Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009).

Oakhill, J. S. et al. β-subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc. Natl Acad. Sci. USA 107, 19237–19241 (2010).

Suzuki, A. et al. Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor α gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the α2 form of AMP-activated protein kinase. Mol. Cell Biol. 27, 4317–4327 (2007).

Kodiha, M., Rassi, J. G., Brown, C. M. & Stochaj, U. Localization of AMP kinase is regulated by stress, cell density and signaling through the MEK→ERK1/2 pathway. Am. J. Physiol. Cell Physiol. 293, C1427–1436 (2007).

Kazgan, N., Williams, T., Forsberg, L. J. & Brenman, J. E. Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase. Mol. Biol. Cell 21, 3433–3442 (2011).

Dorfman, J. & Macara, I. G. STRADα regulates LKB1 localization by blocking access to importin-α, and by association with Crm1 and exportin-7. Mol. Biol. Cell 19, 1614–1626 (2008).

Sebbagh, M., Santoni, M. J., Hall, B., Borg, J. P. & Schwartz, M. A. Regulation of LKB1/STRAD localization and function by E-cadherin. Curr. Biol. 19, 37–42 (2009).

Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).

Tamas, P. et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006).

Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833–843 (2004).

Alessi, D. R., Sakamoto, K. & Bayascas, J. R. Lkb1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).

Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

Dykens, J. A. et al. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 233, 203–210 (2008).

Hawley, S. A. et al. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).

Hardie, D. G. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology 131, 973; author reply 974–975 (2006).

Hardie, D. G. AMP-activated protein kinase as a drug target. Annu. Rev. Pharmacol. Toxicol. 47, 185–210 (2007).

Rothbart, S. B., Racanelli, A. C. & Moran, R. G. Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res. 70, 10299–10309 (2010).

Zang, M. et al. Polyphenols stimulate AMP-activated protein kinase, lower lipids and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55, 2180–2191 (2006).

Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

Pacholec, M. et al. SRT1720, SRT2183, SRT1460 and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340–8351 (2010).

Schmidt, C. GSK/Sirtris compounds dogged by assay artifacts. Nat. Biotechnol. 28, 185–186 (2010).

Canto, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010).

Um, J. H. et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554–563 (2010).

Hundal, R. S. et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49, 2063–2069 (2000).

Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

Halseth, A. E., Ensor, N. J., White, T. A., Ross, S. A. & Gulve, E. A. Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem. Biophys. Res. Commun. 294, 798–805 (2002).

Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

Foretz, M. et al. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 54, 1331–1339 (2005).

Yang, J., Maika, S., Craddock, L., King, J. A. & Liu, Z. M. Chronic activation of AMP-activated protein kinase-α1 in liver leads to decreased adiposity in mice. Biochem. Biophys. Res. Commun. 370, 248–253 (2008).

Zang, M. et al. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J. Biol. Chem. 279, 47898–47905 (2004).

Zhang, B. B., Zhou, G. & Li, C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 9, 407–416 (2009).

Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11, 390–401 (2010).

Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).

Kamada, Y. et al. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507–1513 (2000).

Kamada, Y. et al. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol. Cell Biol. 30, 1049–1058 (2010).

Stephan, J. S., Yeh, Y. Y., Ramachandran, V., Deminoff, S. J. & Herman, P. K. The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc. Natl Acad. Sci. USA 106, 17049–17054 (2009).

Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132–139 (2010).

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

Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates autophagy. PLoS One 5, e15394 (2010).

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

Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

Wang, Z., Wilson, W. A., Fujino, M. A. & Roach, P. J. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol. Cell Biol. 21, 5742–5752 (2001).

Shang, L. et al. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc. Natl Acad. Sci. USA 108, 4788–4793 (2011).

Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).

Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

Liang, J. et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 9, 218–224 (2007).

Bjorklund, M. A. et al. Non-CDK-bound p27 (p27(NCDK)) is a marker for cell stress and is regulated through the Akt/PKB and AMPK-kinase pathways. Exp. Cell Res. 316, 762–774 (2010).

Zagorska, A. et al. New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. Sci. Signal. 3, ra25 (2010).

Carling, D., Zammit, V. A. & Hardie, D. G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217–222 (1987).

Sato, R., Goldstein, J. L. & Brown, M. S. Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc. Natl Acad. Sci. USA 90, 9261–9265 (1993).

Sakamoto, K. & Holman, G. D. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295, E29–37 (2008).

Watt, M. J. et al. Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am. J. Physiol. Endocrinol. Metab. 290, E500–508 (2006).

Ahmadian, M. et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 13, 739–748 (2011).

Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010).

Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

Hardie, D. G. Transcription. Targeting the core of transcription. Science 329, 1158–1159 (2010).

Bass, J. & Takahashi, J. S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

Um, J. H. et al. Activation of 5´-AMP-activated kinase with diabetes drug metformin induces casein kinase Iɛ (CKIɛ)-dependent degradation of clock protein mPer2. J. Biol. Chem. 282, 20794–20798 (2007).

Um, J. H. et al. AMPK regulates circadian rhythms in a tissue- and isoform-specific manner. PLoS One 6, e18450 (2011).

Li, Y. et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13, 376–388 (2011).

Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

Kawaguchi, T., Osatomi, K., Yamashita, H., Kabashima, T. & Uyeda, K. Mechanism for fatty acid 'sparing' effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J. Biol. Chem. 277, 3829–3835 (2002).

Dentin, R., Girard, J. & Postic, C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87, 81–86 (2005).

Bricambert, J. et al. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J. Clin. Invest. 120, 4316–4331 (2010).

Tong, X., Zhao, F., Mancuso, A., Gruber, J. J. & Thompson, C. B. The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation. Proc. Natl Acad. Sci. USA 106, 21660–21665 (2009).

Altarejos, J. Y. & Montminy, M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, 141–151 (2011).

Mair, W. et al. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404–408 (2011).

Hong, Y. H., Varanasi, U. S., Yang, W. & Leff, T. AMP-activated protein kinase regulates HNF4α transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem. 278, 27495–27501 (2003).

Kim, E. et al. Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity. Diabetes 60, 1493–1503 (2011).

Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

Inoue, E. & Yamauchi, J. AMP-activated protein kinase regulates PEPCK gene expression by direct phosphorylation of a novel zinc finger transcription factor. Biochem. Biophys. Res. Commun. 351, 793–799 (2006).

van der Linden, A. M., Nolan, K. M. & Sengupta, P. KIN-29 SIK regulates chemoreceptor gene expression via an MEF2 transcription factor and a class II HDAC. EMBO J. 26, 358–370 (2007).

Chang, S., Bezprozvannaya, S., Li, S. & Olson, E. N. An expression screen reveals modulators of class II histone deacetylase phosphorylation. Proc. Natl Acad. Sci. USA 102, 8120–8125 (2005).

Dequiedt, F. et al. New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases. Mol. Cell Biol. 26, 7086–7102 (2006).

Berdeaux, R. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat. Med. 13, 597–603 (2007).

McGee, S. L. et al. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57, 860–867 (2008).

Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621 (2011).

Wang, B. et al. A hormone-dependent module regulating energy balance. Cell 145, 596–606 (2011).

Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).

Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007).

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

Canto, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).

Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).

Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

Mirouse, V. & Billaud, M. The LKB1/AMPK polarity pathway. FEBS Lett 585, 981–985 (2011).

Watts, J. L., Morton, D. G., Bestman, J. & Kemphues, K. J. The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. Development 127, 1467–1475 (2000).

Martin, S. G. & St Johnston, D. A role for Drosophila LKB1 in anterior–posterior axis formation and epithelial polarity. Nature 421, 379–384 (2003).

Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004).

Jansen, M., Ten Klooster, J. P., Offerhaus, G. J. & Clevers, H. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol. Rev. 89, 777–798 (2009).

Lee, J. H. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020 (2007).

Mirouse, V., Swick, L. L., Kazgan, N., St Johnston, D. & Brenman, J. E. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol. 177, 387–392 (2007).

Zhang, L., Li, J., Young, L. H. & Caplan, M. J. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl Acad. Sci. USA 103, 17272–17277 (2006).

Zheng, B. & Cantley, L. C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc. Natl Acad. Sci. USA 104, 819–822 (2007).

Zhang, L. et al. AMP-activated protein kinase (AMPK) activation and glycogen synthase kinase-3β (GSK-3β) inhibition induce Ca2+-independent deposition of tight junction components at the plasma membrane. J. Biol. Chem. 286, 16879–16890 (2011).

Miyamoto, T. et al. AMP-activated protein kinase phosphorylates Golgi-specific brefeldin A resistance factor 1 at Thr 1337 to induce disassembly of Golgi apparatus. J. Biol. Chem. 283, 4430–4438 (2008).

Nakano, A. et al. AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nat. Cell Biol. 12, 583–590 (2010).

Choi, J. H. et al. The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO Rep. 3, 988–994 (2002).

Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell. Biol. 12, 1115–1122 (2010).

Williams, T., Courchet, J., Viollet, B., Brenman, J. E. & Polleux, F. AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc. Natl Acad. Sci. USA 108, 5849–5854 (2011).

Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M. & Mandelkow, E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297–308 (1997).

Nishimura, I., Yang, Y. & Lu, B. PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116, 671–682 (2004).

Thornton, C., Bright, N. J., Sastre, M., Muckett, P. J. & Carling, D. AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure. Biochem. J. 434, 503–512 (2011).

Amato, S. et al. AMP-activated protein kinase regulates neuronal polarization by interfering with PI3-kinase localization. Science 332, 247–251 (2011).

McDonald, A. et al. Control of insulin granule dynamics by AMPK dependent KLC1 phosphorylation. Islets 1, 198–209 (2009).