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evolution
Pfkfb (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) enzymes are bi-functional enzymes encoded by four different genes (pfkfb1, pfkfb2, pfkfb3, pfkfb4) in vertebrates, phylogenetic analysis of Pfkfb enzymes in vertebrates, overview
malfunction
PFKFB3 enzymes are activated in human cancers
malfunction
Akt inactivation blocks PFKFB2 phosphorylation and fructose 2,6-bisphosphate production
malfunction
Akt inactivation blocks PFKFB2 phosphorylation and fructose 2,6-bisphosphate production
malfunction
knockdown of PFKFB3/iPFK2 in N-43/5 neurons causes a decrease in rates of glycolysis, which is accompanied by increased AMPK phosphorylation, increased AgRP mRNA levels and decreased CART mRNA levels. Overexpression of PFKFB3/iPFK2 in N-43/5 neurons causes an increase in glycolysis, which is accompanied by decreased AMPK phosphorylation and decreased AgRP mRNA levels and increased CART mRNA levels
malfunction
knockdown of PFKFB4 in prostate cancer cells increases p62 and reactive oxygen species, but surprisingly increases autophagic flux. Addition of the reactive oxygen species scavenger N-acetyl cysteine prevents p62 accumulation in PFKFB4-depleted cells. PFKFB4 depletion acts upstream of ATG7 consistent with increased oxidative stress that induces autophagy and p62 upregulation
malfunction
Mb transgenic mice have reduced fructose 2,6-bisphosphate levels, due to cardiac expression of a transgene for a mutant, kinase deficient form of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) which controls the level of fructose 2,6-bisphosphate. Mb hearts are markedly more sensitive to transverse aortic constriction-induced damage showing lower fractional shortening in Mb-TAC mice as well as larger left ventricular end diastolic and end systolic diameters. Cardiac hypertrophy and pulmonary congestion are more severe in Mb-transverse aortic constriction mice, Mb transgene exacerbates transverse aortic constriction-induced increases in cardiac hypertrophy and lung weight, detailed phenotype, overview
malfunction
PFKFB4 inhibition in H-460 cells reduces glycolytic flux to lactate and glutamate. PFKFB4 inhibition in H-460 cells increases apoptosis under normoxic and hypoxic conditions
malfunction
silencing of PFKFB4 results in increased levels of Fru-2,6-P2 in prostate cancer cells, knockdown of PFKFB4 blocks prostate cancer cell growth and remarkably induced regression of prostate tumor xenografts
malfunction
siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. PFKFB3 inhibition completely suppresses cell proliferation and results in increased early and late apoptotic cells. PFKFB3 inhibition results in increased nuclear and cytoplasmic p27 protein but has no effect on p57 or p21. Blockade of cell cycle progression and stimulation of apoptosis by PFKFB3 inhibition is mediated by p27
malfunction
enzyme knockdown inhibits clonogenic growth and enhances paclitaxel sensitivity in ovarian and breast cancer cell lines with wild type TP53
malfunction
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mutations in the phosphatase but not in the kinase domain of PFK-2/FBPase-2 alter sexual development and lead to suppression of the respiratory deficient DELTAcox phenotype
malfunction
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Akt inactivation blocks PFKFB2 phosphorylation and fructose 2,6-bisphosphate production
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malfunction
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knockdown of PFKFB3/iPFK2 in N-43/5 neurons causes a decrease in rates of glycolysis, which is accompanied by increased AMPK phosphorylation, increased AgRP mRNA levels and decreased CART mRNA levels. Overexpression of PFKFB3/iPFK2 in N-43/5 neurons causes an increase in glycolysis, which is accompanied by decreased AMPK phosphorylation and decreased AgRP mRNA levels and increased CART mRNA levels
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metabolism
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glycolytic enzyme is present as testis-specific isoforms, these isoforms are expressed specifically or predominantly in spermatogenic cells, often during the post-meiotic phase, and replace the ubiquitous isozymes that are also present in somatic cells
metabolism
cancer cells use control of PFKFB3 of the important glycolytic pathway to generate ATP
metabolism
expression level of some PFKFB and PFK1 genes in normoxic and hypoxic conditions in glioma cells is mediated by ERN1 signaling system of endoplasmic reticulum stress. Effect of hypoxia on the expression of genes encoded different 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, PFKFB2, PFKFB3 and PFKFB4) and 6-phosphofructo-1-kinase (PFKL, PFKM and PFKP) as well as lactate dehydrogenase in glioma U-87 cells and its subline with suppressed function of ERN1 signaling enzyme, overview
metabolism
expression level of some PFKFB and PFK1 genes in normoxic and hypoxic conditions in glioma cells is mediated by ERN1 signaling system of endoplasmic reticulum stress. Effect of hypoxia on the expression of genes encoded different 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1, PFKFB2, PFKFB3 and PFKFB4) and 6-phosphofructo-1-kinase (PFKL, PFKM and PFKP) as well as lactate dehydrogenase in glioma U-87 cells and its subline with suppressed function of ERN1 signaling enzyme, overview. Increased expression of PFKFB3 and PFKFB4 under hypoxic conditions correlates with strong induction of PFKL expression in control glioma cells only
metabolism
fructose 2,6-bisphosphate is an important metabolite for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1, fructose 2,6-bisphosphate is a powerful allosteric activator of phosphofructokinase 1, PFK-1
metabolism
glucose causes decreased binding of glucokinase to glucokinase regulatory protein, GKRP, translocation from the nucleus and increased binding to 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2 (PFK2/FBPase2) in the cytoplasm, while glucagon causes dissociation of glucokinase from PFK2/FBPase2, concomitant with phosphorylation of PFK2/FBPase2 on Ser32, uptake of glucokinase into the nucleus and increased interaction with GKRP
metabolism
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moderate grade hyperammonemia activates lactate dehydrogenase-4 and 6-phosphofructo-2-kinase to support increased lactate turnover in the brain slices
metabolism
re-feeding increases plasma levels of glucose and insulin and stimulates PFKFB3 expression. Glucose and insulin stimulate PFKFB3 expression, increase glycolysis, and decrease AMPK phosphorylation in clonal hypothalamic neurons
metabolism
the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) comprises well established regulators of glucose metabolism via their synthesis of fructose-2,6 bisphosphate, a potent allosteric activator of 6-phosphofructo-1-kinase. But PFKFB3 and fructose-2,6 bisphosphate function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells
metabolism
upregulation of p62 and autophagy is a response to oxidative stress caused by PFKFB4. PFKFB4 is an autophagy regulator
metabolism
enzyme PFKFB3 is an essential target of epidermal growth factor receptor signaling. PFKFB3 activation is required for glycolysis stimulation upon epidermal growth factor receptor activation. PFKFB3 has a key role in mediating glucose metabolism and survival of NSCLC cells in response to epidermal growth factor receptor signaling
metabolism
PFKFB3 has the highest kinase:phosphatase ratio (710:1) to shunt glucose toward glycolysis, whereas PFKFB4 has more fructose-2,6-bisphosphatase-2 activity (kinase:phosphatase ratio of 4.6:1), redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species. Co-expression of PFKFB3 and PFKFB4 provides sufficient glucose metabolism to satisfy the bioenergetics demand and redox homeostasis requirements of cancer cells
metabolism
PFKFB3 has the highest kinase:phosphatase ratio (710:1) to shunt glucose toward glycolysis, whereas PFKFB4 has more fructose-2,6-bisphosphatase-2 activity (kinase:phosphatase ratio of 4.6:1), redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species. Co-expression of PFKFB3 and PFKFB4 provides sufficient glucose metabolism to satisfy the bioenergetics demand and redox homeostasis requirements of cancer cells. PFKFB4 acts as a protein kinase, regulates steroid receptor coactivator-3 activity and is involved in transcriptional regulation
metabolism
the enzyme binds and activates glucokinase
metabolism
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re-feeding increases plasma levels of glucose and insulin and stimulates PFKFB3 expression. Glucose and insulin stimulate PFKFB3 expression, increase glycolysis, and decrease AMPK phosphorylation in clonal hypothalamic neurons
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metabolism
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glucose causes decreased binding of glucokinase to glucokinase regulatory protein, GKRP, translocation from the nucleus and increased binding to 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2 (PFK2/FBPase2) in the cytoplasm, while glucagon causes dissociation of glucokinase from PFK2/FBPase2, concomitant with phosphorylation of PFK2/FBPase2 on Ser32, uptake of glucokinase into the nucleus and increased interaction with GKRP
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physiological function
PFKFB3 has a role in nuclear signaling
physiological function
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spermatogenesis, both PFK-2 isozymes have specific roles in testis metabolism and physiology, PFK-2 isozyme expression switches from the ubiquitous form, required during proliferative phases, to the testicular form, which is the germ cell-specific one
physiological function
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enzyme acts as an endogenous glucokinase activator. Binding and activation of glucokinase by bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in beta-cells is promoted by glucose, resulting in an enhancement of insulin secretion at stimulatory glucose concentrations, without affecting basal insulin secretion
physiological function
enzyme is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of the enzyme inhibits tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. Enzyme mRNA expression is greater in metastatic prostate cancer compared with primary tumors
physiological function
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is an antagonist of glucokinase inhibition by the competitive glucokinase inhibitor mannoheptulose at increasing glucose concentrations. In combination with chemical activator LY2121260, the enzyme shows additive activation of glucokinase
physiological function
knockdown of isoform PFKFB3/iPFK2 in N-43/5 neurons causes a decrease in rates of glycolysis, which is accompanied by increased AMP-activated protein kinase phosphorylation, increased agouti-related protein mRNA levels and decreased cocaine-amphetamine-related transcript mRNA levels. Overexpression of PFKFB3/iPFK2 in N-43/5 neurons causes an increase in glycolysis, which is accompanied by decreased AMP-activated protein kinase phosphorylation and decreased agouti-related protein mRNA levels and increased cocaine-amphetamine-related transcript mRNA levels
physiological function
enzyme PFKFB3 belongs to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs) that controls the conversion of fructose-6-phosphate to and from fructose-2,6-bisphosphate, a key regulator of the glycolytic enzyme phosphofructokinase-1
physiological function
fructose 2,6-bisphosphate is a positive regulator of the glycolytic enzyme phosphofructokinase
physiological function
in human cancers, loss of PTEN, stabilization of HIF-1alpha and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, 6-phosphofructo-2-kinase(PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate, which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis
physiological function
isozyme PFKFB4 expressed in multiple transformed cells and tumors functions to synthesize fructose 2,6-bisphosphate, PFKFB4 is required for cancer cell survival during the metabolic response to hypoxia, presumably to enable glycolytic production of ATP when the electron transport chain is not fully operational. Isozyme PFKFB4 is overexpressed in human cancers, induced by hypoxia and required for survival and growth of several cancer cell lines
physiological function
PFKFB3 is overexpressed in human cancers, regulated by HIF-1alpha, Akt and PTEN, and required for the survival and growth of multiple cancer types. Role of PFKFB3 in regulating Cdk1- and p27-mediated G1/S blockade and apoptosis
physiological function
possible role of different isozyme PFKFB4 splice variants in cell-specific and/or tissue-specific regulation of glycolysis, role of PFKFB proteins in the control of cancer metabolism. PFKFB4 may be important for cancer cell survival, PFKFB4 plays an essential role in the survival of glioma stem-like cells and of prostate cancer cells. PFKFB4 is known to be a component of the HIF-mediated response to hypoxia, hypoxic induction of PFKFB4 is mediated by a hypoxia response element (HRE) in the promoter region of the PFKFB4 gene
physiological function
role for PFKFB3/iPFK2 in regulating glycolysis in hypothalamic neurons, in the context of neuronal glucose sensing and neuropeptide expression. PFKFB3/iPFK2 responds to re-feeding, which in turn stimulates hypothalamic glycolysis and decreases hypothalamic AMPK phosphorylation and alters neuropeptide expression in a pattern that is associated with suppression of food intake
physiological function
role for phosphofructo 2-kinase/fructose 2,6-bisphosphate (PFK2/FBPase2) as a cytoplasmic binding partner of glucokinase and glucagon-induced uptake of glucokinase to the nucleus
physiological function
role of PFKFB proteins in the control of cancer metabolism
physiological function
role of PFKFB proteins in the control of cancer metabolism. Liver, muscle and fetal isoform variants of PFKFB1 (L-PFK2, M-PFK2 and F-PFK2 respectively) are transcribed from the same gene, but only L-PFK2 contains a serine residue in position 32 of its C-terminal regulatory domain. This is consistent with its specific physiological role as liver cells need to modulate Fru-2,6-P2 levels to facilitate the production of glucose to fulfill the metabolic demand of other tissues. Response to glucagon, cyclic AMP-dependent protein kinase (PKA) phosphorylates Ser32 in the liver isoform of PFKFB1, leads to inactivation of its PFK-2 activity while activating its FBPase-2 function. This decreases glycolytic flux while increasing gluconeogenesis in liver cells While phosphorylation of L-PFK2 results in a decrease in its kinase activity, phosphorylation of H-PFK2 results in an increase in this activity
physiological function
role of PFKFB proteins in the control of cancer metabolism. PFKFB3 is known to be a component of the HIF-mediated response to hypoxia. PFKFB3 is a hypoxia-inducible gene that is stimulated through the interaction of HIF-1alpha with a consensus HRE within its promoter region
physiological function
the enzyme is involved in the regulation of glycolysis, it catalyzes the synthesis and the degradation of beta-D-fructose 2,6-bisphosphate, the most potent allosteric activator of phosphofructokinase 1 (Pfk1), a key glycolytic enzyme. By producing fructose 2,6-bisphosphate, Pfkfb enzymes allow glycolysis to proceed, while by degrading fructose 2,6-bisphosphate they block glycolysis. As major regulators of glycolysis, Pfkfb enzymes are involved in cancer: tumor cells have a higher glycolytic rate compared to normal cells, even in the presence of adequate oxygen levels (Warburg effect) and several cancer cell lines express elevated levels of Pfkfb enzymes
physiological function
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the PFK2 domain of PFK2/FBPase2 regulates glycolysis to maintain the pyruvate pool for lactate synthesis
physiological function
the putative autophagy stimulator, isozyme PFKFB4, drives flux through pentose phosphate pathway. PFKFB4 suppresses oxidative stress and p62 accumulation, without which autophagy is stimulated likely as a reactive oxygen species detoxification response. Genes whose loss enhanced p62 elimination are putative negative regulators of autophagy and the bi-functional enzyme PFKFB4 highly inhibits p62 elimination. PFKFB4 is an autophagy regulator. PFKFB4 suppresses autophagy and p62 accumulation by mitigating reactive oxygen species
physiological function
both a PFKFB3 inhibitor or PFKFB3 silencing by siRNA suppress the basal and the H2O2-induced autophagy concomitantly with the inhibition of AMPK activity. Overexpression of wild-type PFKFB3 promotes H2O2-induced autophagy, but mutant K472/473A, which lost nuclear localizing property, inhibits the autophagic process. The K472/473A mutant stimulates more lactate production, and decreases the activity of AMPK compared to the wild-type
physiological function
overexpression of microRNA miR-26b represses PFKFB3 mRNA and protein levels followed by modulation of the expression of glycolytic components such as LDHA, GLUT-1 and markers of invasion and cell cycle such as MMP-9, MMP-2, cyclin D1 and p27. The binding site for miR-26b is predicted in the 3'-untranslated region of the PFKFB3 gene
physiological function
Transforming growth factor TGFbeta1 induces isoform PFKFB3 expression and stimulates glycolysis in Panc1 cells. siRNA silencing of PFKFB3 prevents the stimulation of glycolysis and in vitro invasion ability of Panc1 cells by TGFbeta1. PFKFB3 silencing suppresses the TGFbeta1-mediated induction of the Snail protein
physiological function
tumor suppressor p53 regulates the expression of PFKFB4 and p53-deficient cancer cells are highly dependent on the function of the enzyme. Depletion of PFKFB4 from p53-deficient cancer cells increases levels of fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 is also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Depletion of PFKFB4-attenuates cellular biosynthetic activity and results in the accumulation of reactive oxygen species and cell death in the absence of p53. Silencing of PFKFB4-induces apoptosis in p53-deficient cancer cells in vivo and interferes with tumor growth
physiological function
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers
physiological function
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role for PFKFB3/iPFK2 in regulating glycolysis in hypothalamic neurons, in the context of neuronal glucose sensing and neuropeptide expression. PFKFB3/iPFK2 responds to re-feeding, which in turn stimulates hypothalamic glycolysis and decreases hypothalamic AMPK phosphorylation and alters neuropeptide expression in a pattern that is associated with suppression of food intake
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physiological function
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role for phosphofructo 2-kinase/fructose 2,6-bisphosphate (PFK2/FBPase2) as a cytoplasmic binding partner of glucokinase and glucagon-induced uptake of glucokinase to the nucleus
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