Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes

Tamás, Péter; Hawley, Simon A.; Clarke, Rosemary G.; Mustard, Kirsty J.; Green, Kevin; Hardie, D. Grahame; Cantrell, Doreen A.

doi:10.1084/jem.20052469

Cited by 305 publications

(233 citation statements)

References 30 publications

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“…Based on our data, cells respond by reducing CPT1A expression, stably suppressing ␤-oxidation throughout the proliferative response. In this regard, it is also noteworthy that activation of human and murine T lymphocytes stimulated the AMP-activated protein kinase, a key regulator of cellular bioenergetic homeostasis that can also enhance ␤-oxidation in muscle (41,42). The suppression of CPT1A expression that we observed after antigen-induced stimulation of T lymphocytes would explain how these cells undergo simultaneous activation of AMP-activated protein kinase and inhibition of ␤-oxidation.…”

Section: Discussionmentioning

confidence: 68%

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

DeBerardinis

Lum

Thompson

2006

Journal of Biological Chemistry

201

163

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An abundant supply of extracellular nutrients is believed to be sufficient to suppress catabolism of cellular macromolecules. Here we show that, despite abundant extracellular nutrients, interleukin-3-deprived hematopoietic cells begin to catabolize intracellular lipids. Constitutive Akt activation blunts the increased ␤-oxidation that accompanies growth factor withdrawal, and in growth factor-replete cells, phosphatidylinositol 3-kinase (PI3K) signaling is required to suppress lipid catabolism. Surprisingly, PI3K and Akt exert these effects by suppressing expression of the ␤-oxidation enzyme carnitine palmitoyltransferase 1A (CPT1A). Cells expressing a short hairpin RNA against CPT1A fail to induce ␤-oxidation in response to growth factor withdrawal and are unable to survive glucose deprivation. When CPT1A is constitutively expressed, growth factor stimulation fails to repress ␤-oxidation. As a result, both net lipid synthesis and cell proliferation are diminished. Together, these results demonstrate that modulation of CPT1A expression by PI3K-dependent signaling is the major mechanism by which cells suppress ␤-oxidation during anabolic growth.Single-cell eukaryotes like yeast autonomously regulate their uptake of nutrients from the extracellular environment. In such organisms, cellular metabolism is regulated primarily in response to nutrient availability (1). In contrast, it has been proposed that mammalian cells do not take up and metabolize nutrients without instruction from extracellular signals. These signals, which include cytokines and other lineage-specific growth factors, stimulate signal transduction pathways that orchestrate cellular metabolism through effects on gene expression and enzyme kinetics. Together, these signal-induced changes function to direct uptake and utilization of nutrients, channeling metabolites into biosynthetic pathways (2-4). One important example of this phenomenon occurs during lymphocyte stimulation, where receptor-induced signaling directly increases glucose transport, glycolysis, lactate production, and synthesis of lipids (5-9).Many of the metabolic changes elicited by growth factors result from activation of the phosphatidylinositol 3-kinase (PI3K)/Akt 4 signaling system. In this pathway, binding of a growth factor to its surface receptor induces activation of the lipid kinase PI3K, which phosphorylates phosphatidylinositol species (10). End products of PI3K activity recruit the serine/ threonine kinase Akt to the plasma membrane where it becomes a substrate for phosphorylation and activation by phosphoinositide-dependent protein kinase 1 and other regulatory kinases (10). The metabolic effects of growth factorinduced PI3K/Akt stimulation include increases in glucose import and glycolysis, which fuel the bioenergetic and biosynthetic activities of growing cells (11-13). Constitutive activation of PI3K and/or Akt through a variety of genetic mechanisms is a common transforming event in human cancer, including some 25% of breast carcinoma and 30% of colon carcinoma (14 -1...

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Section: Discussionmentioning

confidence: 68%

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

DeBerardinis

Lum

Thompson

2006

Journal of Biological Chemistry

201

163

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“…Inhibiting endogenous LKB1 does not prevent AMPK activation by thrombin, although LKB1 can phosphorylate AMPK in response to other stimuli in these cells. In T lymphocytes, AMPK can be activated by cellular stress inducing a high AMP: ATP ratio by a mechanism that is insensitive to STO-609, likely through LKB1 (40). However, triggering the T cell antigen receptor complex in these cells promotes an influx of Ca 2ϩ and activates AMPK via a CaMKK␤-specific route.…”

Section: Discussionmentioning

confidence: 99%

Muscarinic Receptor Activation of AMP-activated Protein Kinase Inhibits Orexigenic Neuropeptide mRNA Expression

Thornton

Sardini

Carling

2008

Journal of Biological Chemistry

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AMP-activated protein kinase (AMPK) plays a crucial role in both cellular and whole body energy homeostasis. Here we demonstrate that the muscarinic receptor agonist carbachol activates AMPK␣1-containing complexes in the human SH-SY5Y cell line via a mechanism specific for the AMPK upstream kinase, Ca 2؉ /calmodulin-dependent protein kinase kinase ␤. Activation of AMPK inhibits mRNA expression of the orexigenic neuropeptides Agouti-related peptide and melanin-concentrating hormone but surprisingly has no effect on neuropeptide Y mRNA, a neuropeptide previously shown to be regulated by AMPK. Rather than restoring mRNA levels to baseline, pharmacological inhibition of Ca 2؉ /calmodulin-dependent protein kinase kinase ␤ or AMPK greatly increases Agouti-related peptide and melanin-concentrating hormone mRNA expression. These data support a hypothesis that modulating basal AMPK activity in the hypothalamus is essential for maintaining tight regulation of pathways contributing to food intake. AMP-activated protein kinase (AMPK)2 is a key metabolic enzyme in the regulation of energy homeostasis (1). At a cellular level, AMPK is activated in response to diverse physiological and pathological stimuli that cause ATP depletion. Subsequently, AMPK acts to maintain the AMP:ATP ratio through inhibition of pathways that catabolize ATP and promotion of ATP-generating pathways (2).AMPK is a heterotrimeric serine/threonine kinase, comprising a catalytic ␣ subunit and regulatory ␤ and ␥ subunits. There are two ␣, two ␤, and three ␥ isoforms, and all 12 ␣␤␥ combinations have been identified in vivo. Activation of AMPK requires the action of upstream kinases that phosphorylate threonine residue 172 within the T-loop activation domain of the ␣ subunit (2). Three AMPK kinases have been identified to date. LKB1 is a tumor suppressor kinase linked to the rare hereditary cancer predisposition, Peutz-Jeghers syndrome (3).In complex with regulatory proteins STE20-related adaptor (STRAD␣) and MO25, LKB1 phosphorylates and activates AMPK (4, 5), possibly in response to changes in the AMP:ATP ratio. In addition, Ca 2ϩ /calmodulin-dependent protein kinase kinase ␤ (CaMKK␤) has also been identified as an AMPK kinase (6 -8), phosphorylating and activating AMPK in response to elevated intracellular Ca 2ϩ concentrations. Finally, transforming growth factor-␤-activated kinase 1 (TAK1) was very recently implicated in the regulation of AMPK activity in cells and in the heart, although its regulation remains unknown (9, 10). Thus, AMPK is well equipped to respond to a diverse range of stimuli.AMPK is expressed ubiquitously, and recent findings have stimulated interest in roles for neuronal AMPK (11). Although prolonged pharmacological activation of AMPK in neuroblastoma cells is reported to induce apoptosis (12), increasing evidence points toward a role for AMPK in neuroprotection. AMPK is activated in response to excitotoxic stimuli in hippocampal neurons, and inhibiting AMPK potentiates neurodegeneration (13). More recently, AMPK was shown to intera...

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“…Recent evidence demonstrates that ADP can also regulate AMPK activation by protecting AMPK from dephosphorylation (Xiao et al 2011). In addition, AMPK activity can be modulated independently of AMP by activation of CaMKKb due to increasing intracellular Ca 2C levels , Tamas et al 2006, Sanders et al 2007 and by ubiquitination and degradation (Qi et al 2008). A simplified cartoon illustrating the structure and regulation of AMPK activity is shown in Fig.…”

Section: Structure and Regulationmentioning

confidence: 99%

AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of a or b subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

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Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes

Cited by 305 publications

References 30 publications

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

Muscarinic Receptor Activation of AMP-activated Protein Kinase Inhibits Orexigenic Neuropeptide mRNA Expression

AMP-activated protein kinase pathway and bone metabolism

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