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:10.1083/jcb1742oia4

Cited by 58 publications

(77 citation statements)

References 19 publications

(23 reference statements)

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“…The LKB1-deficient thymocytes showed a reproducible two to threefold decrease in AMPK phosphorylation relative to their controls ( Figure 6A). Previous analyses had shown that depletion of the intracellular ATP pool by treatment with the glucose analog, 2-deoxyglucose, normally results in a rapid increase in AMPK phosphorylation [35]. Although this was the case in wild-type DP thymocytes, 2-deoxyglucose failed npg to increase AMPK phosphorylation in LKB1-deficient DP thymocytes ( Figure 6B), suggesting that LKB1 is required for AMPK activation in thymocytes on energy stress.…”

Section: Lkb1 Controls Dp Thymocyte Survival Through Activation Of Ampkmentioning

confidence: 53%

The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression

Cao

Liu

et al. 2009

Cell Res

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LKB1 is a serine/threonine kinase that directly activates the energy sensor AMP-activated protein kinase (AMPK) in response to bioenergetic stress, and mainly acts as a tumor suppressor that controls cell polarity and proliferation. Although LKB1 is expressed in multiple tissues including the thymus and the spleen, its roles in T-cell development and function remain unknown. Here, we show that T-cell-specific deletion of LKB1 resulted in reduced survival of double-positive (DP) thymocytes and impaired generation of both CD4 and CD8 single-positive thymocytes. Disruption of LKB1 not only prevented the activation of AMPK but also impaired the expression of anti-apoptotic protein Bcl-XL. Importantly, ectopic expression of either Bcl-XL or the constitutively active AMPK mutant significantly rescued DP thymocytes from LKB1 deficiency-induced cell death. Moreover, ectopic expression of the constitutively active AMPK mutant was found to restore the expression of Bcl-XL in LKB1-deficient DP thymocytes. These findings identify LKB1 as a critical factor for the survival of DP thymocytes through regulation of AMPK activation and Bcl-XL expression.

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Section: Lkb1 Controls Dp Thymocyte Survival Through Activation Of Ampkmentioning

confidence: 53%

The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression

Cao

Liu

et al. 2009

Cell Res

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“…3A, treatment of HUVEC with itraconazole increased the phosphorylation of AMPKα at Thr172 within 5 min of drug treatment, with maximal activation occurring 15 min after drug treatment; after that time levels dropped slightly but remained elevated compared with control. The level of AMPK phosphorylation induced by itraconazole at 15 min was similar to that of a positive control compound, thapsigargin (30). Importantly, phosphorylation of the mTOR substrate S6K did not begin to decrease until 15 min after itraconazole treatment and was maximally inhibited after 30 min.…”

Section: Knockdown Of Vdac1 In Huvec Phenocopies the Effects Of Itracmentioning

confidence: 59%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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“…4B) suggests that glucose may be particularly limiting in the early phases of T cell activation. Consistent with glucose limitation early in T cell activation, Tamás et al (34) recently showed an important role for 5ЈAMP-activated protein kinase activation following TCR stimulation, which may promote more efficient ATP generation or use of alternative fuels while Glut1 protein is synthesized and glucose uptake increases to meet cellular demands. Although increases in energy availability are necessary for early T cell activation, maintaining the appropriate balance of nutrient uptake and energy production is also critical for T cell homeostasis as increased glucose uptake led to possible immune pathology with age.…”

Section: Discussionmentioning

confidence: 92%

Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

Jacobs

Herman

MacIver

et al. 2008

The Journal of Immunology

704

766

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T cell activation potently stimulates cellular metabolism to support the elevated energetic and biosynthetic demands of growth, proliferation, and effector function. We show that glucose uptake is limiting in T cell activation and that CD28 costimulation is required to allow maximal glucose uptake following TCR stimulation by up-regulating expression and promoting the cell surface trafficking of the glucose transporter Glut1. Regulation of T cell glucose uptake and Glut1 was critical, as low glucose prevented appropriate T cell responses. Additionally, transgenic expression of Glut1 augmented T cell activation, and led to accumulation of readily activated memory-phenotype T cells with signs of autoimmunity in aged mice. To further examine the regulation of glucose uptake, we analyzed CD28 activation of Akt, which appeared necessary for maximal glucose uptake of stimulated cells and which we have shown can promote Glut1 cell surface trafficking. Consistent with a role for Akt in Glut1 trafficking, transgenic expression of constitutively active myristoylated Akt increased glucose uptake of resting T cells, but did not alter Glut1 protein levels. Therefore, CD28 appeared to promote Akt-independent up-regulation of Glut1 and Akt-dependent Glut1 cell surface trafficking. In support of this model, coexpression of Glut1 and myristoylated Akt transgenes resulted in a synergistic increase in glucose uptake and accumulation of activated T cells in vivo that were largely independent of CD28. Induction of Glut1 protein and Akt regulation of Glut1 trafficking are therefore separable functions of CD28 costimulation that cooperate to promote glucose metabolism for T cell activation and proliferation.

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

Cited by 58 publications

References 19 publications

The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression

The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

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