AMP‐activated protein kinase – development of the energy sensor concept DOI Open Access
D. Grahame Hardie,

Simon A. Hawley,

John W. Scott

et al.

The Journal of Physiology, Journal Year: 2006, Volume and Issue: 574(1), P. 7 - 15

Published: April 28, 2006

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or accelerate consumption muscle contraction). Any decline in cellular energy status accompanied a rise the AMP: ratio, and this activates AMPK complex sensitive mechanism involving antagonistic binding of nucleotides to two sites regulatory gamma subunits AMPK. Once activated stress, catabolic pathways generate ATP, while inhibiting cell growth biosynthesis other processes consume ATP. While system probably evolved single-celled eukaryotes maintain balance at level, multicellular organisms its role has become adapted so it also involved maintaining whole body balance. Thus, regulated hormones cytokines, especially adipokines leptin adiponectin, increasing expenditure regulating food intake. Some may activate an LKB1-independent Ca2+/calmodulin dependent protein kinase kinases. Low levels activation are likely play current global obesity Type 2 diabetes, target for widely used antidiabetic drug metformin.

Language: Английский

AMPK: a nutrient and energy sensor that maintains energy homeostasis DOI
D. Grahame Hardie, Fiona A. Ross,

Simon A. Hawley

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2012, Volume and Issue: 13(4), P. 251 - 262

Published: March 22, 2012

Language: Английский

Citations

3952
AMPK: guardian of metabolism and mitochondrial homeostasis DOI
Sébastien Herzig, Reuben J. Shaw

Nature Reviews Molecular Cell Biology, Journal Year: 2017, Volume and Issue: 19(2), P. 121 - 135

Published: Oct. 4, 2017

Language: Английский

Citations

2946
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism DOI
Maria M. Mihaylova, Reuben J. Shaw

Nature Cell Biology, Journal Year: 2011, Volume and Issue: 13(9), P. 1016 - 1023

Published: Sept. 1, 2011

Language: Английский

Citations

2645
The selectivity of protein kinase inhibitors: a further update DOI

Jenny Bain,

Lorna Plater,

Matt Elliott

et al.

Biochemical Journal, Journal Year: 2007, Volume and Issue: 408(3), P. 297 - 315

Published: Nov. 28, 2007

The specificities of 65 compounds reported to be relatively specific inhibitors protein kinases have been profiled against a panel 70–80 kinases. On the basis this information, effects that we studied in cells and other data literature, recommend use following small-molecule inhibitors: SB 203580/SB202190 BIRB 0796 used parallel assess physiological roles p38 MAPK (mitogen-activated kinase) isoforms, PI-103 wortmannin inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 with Src-I1 (Src inhibitor-1) Src family members; PD 184352 0325901 MKK1 (MAPK kinase-1) plus MKK5, Akt-I-1/2 activation PKB (protein kinase B/Akt), rapamycin TORC1 [mTOR (mammalian target rapamycin)–raptor (regulatory associated mTOR) complex], CT 99021 GSK3 (glycogen synthase 3), BI-D1870 SL0101 FMK (fluoromethylketone) RSK (ribosomal S6 kinase), D4476 CK1 (casein 1), VX680 Aurora kinases, roscovitine as pan-CDK (cyclin-dependent inhibitor. We also identified harmine potent inhibitor DYRK1A (dual-specificity tyrosine-phosphorylated -regulated 1A) vitro. results further emphasized need for considerable caution using these enzymes. Despite being widely, many analysed were too non-specific useful conclusions made, than exclude involvement particular cellular processes.

Language: Английский

Citations

2474
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy DOI
D. Grahame Hardie

Nature Reviews Molecular Cell Biology, Journal Year: 2007, Volume and Issue: 8(10), P. 774 - 785

Published: Aug. 22, 2007

Language: Английский

Citations

2161
The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin DOI Open Access
Reuben J. Shaw, Katja Lamia,

Debbie S. Vasquez

et al.

Science, Journal Year: 2005, Volume and Issue: 310(5754), P. 1642 - 1646

Published: Nov. 25, 2005

The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. deletion of LKB1 in the liver adult mice resulted nearly complete loss activity. Loss function hyperglycemia with increased gluconeogenic lipogenic expression. In LKB1-deficient livers, TORC2, transcriptional coactivator CREB (cAMP response element-binding protein), was dephosphorylated entered nucleus, driving expression peroxisome proliferator-activated receptor-gamma 1alpha (PGC-1alpha), turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha normalized blood glucose levels deleted indicating that is critical target LKB1/AMPK signals regulation Finally, we show metformin, one most widely prescribed type 2 diabetes therapeutics, requires to lower levels.

Language: Английский

Citations

1915
The LKB1–AMPK pathway: metabolism and growth control in tumour suppression DOI
David B. Shackelford, Reuben J. Shaw

Nature reviews. Cancer, Journal Year: 2009, Volume and Issue: 9(8), P. 563 - 575

Published: July 24, 2009

Language: Английский

Citations

1766
Butyrate Enhances the Intestinal Barrier by Facilitating Tight Junction Assembly via Activation of AMP-Activated Protein Kinase in Caco-2 Cell Monolayers DOI Creative Commons
Luying Peng,

Zhongrong Li,

Robert S. Green

et al.

Journal of Nutrition, Journal Year: 2009, Volume and Issue: 139(9), P. 1619 - 1625

Published: July 23, 2009

Language: Английский

Citations

1632
AMPK in Health and Disease DOI
Gregory R. Steinberg, Bruce E. Kemp

Physiological Reviews, Journal Year: 2009, Volume and Issue: 89(3), P. 1025 - 1078

Published: July 1, 2009

The function and survival of all organisms is dependent on the dynamic control energy metabolism, when demand matched to supply. AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator signals that balance through regulation multiple biochemical pathways in eukaryotes. In this review, we begin with discovery AMPK family discuss recent structural studies have revealed molecular basis for AMP binding enzyme's γ subunit. AMPK's involves autoinhibitory features phosphorylation both catalytic α subunit β-targeting We review role at cellular level examination its many substrates how it controls balance. look integrates stress responses such exercise well nutrient hormonal food intake, expenditure, substrate utilization whole body level. Lastly, possible common diseases new age drugs targeting signaling.

Language: Английский

Citations

1594
AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance DOI Creative Commons
Daniel Garcia, Reuben J. Shaw

Molecular Cell, Journal Year: 2017, Volume and Issue: 66(6), P. 789 - 800

Published: June 1, 2017

Language: Английский

Citations

1545