14-3-3s regulate fructose-2,6-bisphosphate levels by binding to PKB-phosphorylated cardiac fructose-2,6-bisphosphate kinase/phosphatase

Rubio, Mercedes Pozuelo

doi:10.1093/emboj/cdg363

Cited by 80 publications

(33 citation statements)

References 47 publications

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“…29 It is under complex regulation: its activity depends on substrate availability; it is activated by low energy charge and high levels of fructose-2,6,-bisphosphate (F-2,6-P 2 ); and it is inhibited by elevated levels of citrate, ATP, and acidic pH. The kinase activity of PFKFB2 (the myocardial isoform of PFK2) is activated by phosphorylation at S483, which is known to be under the influence of AKT, 30, 31 which is activated by the critical regulator of exercise-induced cardiac growth, IGF-1. 20, 32 Notably, both cardiac AKT phosphorylation and plasma IGF-1 were elevated in exercise-adapted mice (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Gibb¹,

Epstein²,

et al. 2017

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Background Exercise promotes metabolic remodeling in the heart, which is associated with physiologic cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiologic cardiac growth. Methods We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, upon exercise adaptation and recovery there was an increase in myocardial phosphofructokinase activity and glycolysis. Cardiac-specific expression of a kinase-deficient PFK2 transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient PFK2 in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiologic cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions Exercise-induced decreases in glycolytic activity stimulate physiologic cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

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Section: Resultsmentioning

confidence: 99%

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Gibb¹,

Epstein²,

et al. 2017

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“…It has been well identified that both PI3K/Akt/mTOR and STAT3 are the key players associated with the Warburg effect25262728424344. These pathways upregulate or activate the center molecule HIF1α which directly or indirectly regulate the expression of genes that code for glycolytic enzymes and enzymes that convert glucose into lactate, leading to an increase in aerobic glycolysis454647.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Qin

Lin

Cao

et al. 2017

Sci Rep

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Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways.

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“…To purify 14-3-3 proteins from Giardia or Drosophila on GST-difopein, 3 mg of soluble proteins were incubated with 15 µg of glutathione-sepharose immobilized GST or GST-difopein in HT buffer at 4°C for 2 h. After extensive washes with HT buffer, the 14-3-3 proteins were eluted with 100 µl of 2 mM A8Ap synthetic phosphopeptide (ARAApSAPA, where pS is a phosphoserine) reproducing a 14-3-3 binding motif [26], in HT buffer. An aliquot of eluted material was run in SDS-PAGE and subjected to immunoblot as described above.…”

Section: Methodsmentioning

confidence: 99%

Interkingdom Complementation Reveals Structural Conservation and Functional Divergence of 14-3-3 Proteins

et al. 2013

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The 14-3-3s are small acidic cytosolic proteins that interact with multiple clients and participate in essential cellular functions in all eukaryotes. Available structural and functional information about 14-3-3s is largely derived from higher eukaryotes, which contain multiple members of this protein family suggesting functional specialization. The exceptional sequence conservation among 14-3-3 family members from diverse species suggests a common ancestor for 14-3-3s, proposed to have been similar to modern 14-3-3ε isoforms. Structural features of the sole family member from the protozoan Giardia duodenalis (g14-3-3), are consistent with this hypothesis, but whether g14-3-3 is functionally homologous to the epsilon isoforms is unknown. We use inter-kingdom reciprocal functional complementation and biochemical methods to determine whether g14-3-3 is structurally and functionally homologous with members of the two 14-3-3 conservation groups of the metazoan Drosophila melanogaster. Our results indicate that although g14-3-3 is structurally homologous to D14-3-3ε, functionally it diverges presenting characteristics of other 14-3-3s. Given the basal position of Giardia in eukaryotic evolution, this finding is consistent with the hypothesis that 14-3-3ε isoforms are ancestral to other family members.

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14-3-3s regulate fructose-2,6-bisphosphate levels by binding to PKB-phosphorylated cardiac fructose-2,6-bisphosphate kinase/phosphatase

Cited by 80 publications

References 47 publications

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

Interkingdom Complementation Reveals Structural Conservation and Functional Divergence of 14-3-3 Proteins

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