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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stimulation of heart glycolysis by insulin and ischemia involves the recruitment of the glucose transporter GLUT4 to the plasma membrane and the activation of 6-phosphofructo-2-kinase (PFK-2), which in turn increases the concentration of fructose 2,6-bisphosphate, a well-known stimulator of glycolysis. This review focuses on the mechanisms responsible for PFK-2 activation by insulin and ischemia in heart. Heart PFK-2 is phosphorylated by various protein kinases, including protein kinase B (PKB), thought to mediate most, if not all, short-term effects of insulin, and the AMP-activated protein kinase (AMPK), known to be activated under anaerobic conditions. We found that PKB is not required for PFK-2 activation by insulin and we partially purified an insulin-sensitive PFK-2 kinase, that differs from PKB and from other insulin-stimulated protein kinases. We also demonstrated that AMPK mediates PFK-2 activation by ischemia. Finally, our study of the interaction between the signaling pathways of insulin and ischemia revealed opposite effects on signaling. Intracellular acidosis induced by ischemia inhibited insulin signaling, whereas insulin pretreatment antagonized AMPK activation by ischemia.
J Mol Cell Cardiol 2002 Sep
PMID:Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. 1239 81

Abnormally high rates of fatty acid metabolism is an important contributor to the severity of ischemic heart disease. During and following myocardial ischemia a number of alterations in fatty acid oxidation occur that result in an excessive amount of fatty acids being used as a fuel source by the heart. This contributes to a decrease in cardiac efficiency both during and following the ischemic episode. Central to the regulation of fatty acid oxidation in the heart is malonyl CoA, which is a potent endogenous inhibitor of mitochondrial fatty acid uptake. The levels of malonyl CoA are regulated both by its synthesis by acetyl CoA carboxylase (ACC) and its degradation by malonyl CoA decarboxylase (MCD). ACC is in turn controlled by AMP-activated protein kinase (AMPK), which acts as a fuel gauge in the heart. The control of these enzymes are altered during ischemia, such that malonyl CoA levels in the heart decrease, resulting in an increased relative contribution of fatty acids to oxidative metabolism. Activation of AMPK during and following ischemia appears to be centrally involved in this decrease in malonyl CoA. Clinical evidence is now accumulating that show that inhibition of fatty acid oxidation is an effective approach to treating ischemic heart disease. As a result, modulation of fatty acid oxidation by targeting the enzymes controlling malonyl CoA may be a novel approach to treating angina pectoris and acute myocardial infarction. This paper will discuss some of the molecular changes that occur in fatty acid oxidation in the ischemic heart and will include a discussion of the important role of malonyl CoA in this process.
J Mol Cell Cardiol 2002 Sep
PMID:Malonyl CoA control of fatty acid oxidation in the ischemic heart. 1239 82

By phosphorylating target proteins, AMP-activated protein kinase (AMPK) inhibits ATP-utilizing proteins and activates ATP-synthesizing proteins, thereby increasing ATP synthesis under conditions such as hypoxia and ischemia. It has been proposed that AMPK also phosphorylates and inhibits creatine kinase (CK), the enzyme which catalyzes the reversible transfer of a phosphoryl group between creatine and ADP. Here, we examine the hypothesis that AMPK inactivates CK activity under three conditions where [AMP] and AMP-dependent AMPK velocity increase: increased workload both in the isolated rat heart and in the living rat, hypoxia in the living rat heart and low-flow ischemia in the isolated red blood cell perfused rat heart. For the experiments varying workload in the isolated rat heart (both ejecting and isovolumic models), we also changed oxidizable substrate available to the isolated heart in order to vary the [AMP]/[ATP]. CK reaction velocity in the intact rat heart was directly measured using (31)P magnetization transfer. The metabolically active AMP and ATP pools were determined from (31)P NMR measurements and we calculate AMP-dependent AMPK velocity from the Michaelis-Menten relationship. We found that under normoxic conditions where [AMP] and AMPK velocity increase, the linear relationship between CK and AMPK velocities is positive, not inverse. Under conditions of low pO(2) (hypoxia and low-flow ischemia), CK velocity fell 2-4-fold while the increase in AMP-activated AMPK activity was modest. This analysis illustrates the complex nature of AMPK regulation in the heart.
J Mol Cell Cardiol 2002 Sep
PMID:Is creatine kinase a target for AMP-activated protein kinase in the heart? 1239 83

The AMP-activated protein kinase (AMPK) is a key enzyme involved in the regulation of lipid and glucose metabolism. There are multiple isoforms of the three subunits of this enzymatic complex, each encoded by a different gene in humans. We have investigated the PRKAB2 gene encoding the beta2 subunit, which is located on chromosome 1q within a region linked with type 2 diabetes mellitus (T2DM) in the Pima Indians and four different Caucasian populations. The gene consists of eight exons spanning about 15 kb, and we detected nine variants in the introns and 3' UTR, including eight informative single nucleotide polymorphisms (SNPs) and one rare 4 bp insertion/deletion. In an analysis of representative markers in selected Pima Indians including 149 diabetic cases (onset age < 25 years) and 150 controls (at least 45 years old, with normal glucose tolerance), we found no evidence for association of this locus with T2DM. We conclude that variants in PRKAB2 are unlikely to contribute to the disease susceptibility in Pima Indians.
Mol Cell Probes 2002 Dec
PMID:Variant screening of PRKAB2, a type 2 diabetes mellitus susceptibility candidate gene on 1q in Pima Indians. 1249 Jan 43

We have recently shown that conditions known to activate AMP-activated protein kinase (AMPK) in primary beta-cells can trigger their apoptosis. The present study demonstrates that this is also the case in the MIN6 beta-cell line, which was used to investigate the underlying mechanism. Sustained activation of AMPK was induced by culture with the adenosine analogue AICA-riboside or at low glucose concentrations. Both conditions induced a sequential activation of AMPK, c-Jun-N-terminal kinase (JNK) and caspase-3. The effects of AMPK on JNK activation and apoptosis were demonstrated by adenoviral expression of constitutively active AMPK, a condition which reproduced the earlier-described AMPK-dependent effects on pyruvate kinase and acetyl-coA-carboxylase. The effects of JNK activation on apoptosis were demonstrated by the observations that (i). its inhibition by dicumarol prevented caspase-3 activation and apoptosis, (ii). adenoviral expression of the JNK-interacting scaffold protein JIP-1/IB-1 increased AICA-riboside-induced JNK activation and apoptosis. In primary beta-cells, AMPK activation was also found to activate JNK, involving primarily the JNK 2 (p54) isoform. It is concluded that prolonged stimulation of AMPK can induce apoptosis of insulin-producing cells through an activation pathway that involves JNK, and subsequently, caspase-3.
J Mol Endocrinol 2003 Apr
PMID:AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase. 1268 39

Members of the Snf1/AMP-activated protein kinase family are activated under conditions of nutrient stress by a distinct upstream kinase. Here we present evidence that the yeast Pak1 kinase functions as a Snf1-activating kinase. Pak1 associates with the Snf1 kinase in vivo, and the association is greatly enhanced under glucose-limiting conditions when Snf1 is active. Snf1 kinase complexes isolated from pak1Delta mutant strains show reduced specific activity in vitro, and affinity-purified Pak1 kinase is able to activate the Snf1-dependent phosphorylation of Mig1 in vitro. Purified Pak1 kinase promotes the phosphorylation of the Snf1 polypeptide on threonine 210 within the activation loop in vitro, and an increased dosage of the PAK1 gene causes increased Snf1 threonine 210 phosphorylation in vivo. Deletion of the PAK1 gene does not produce a Snf phenotype, suggesting that one or more additional protein kinases is able to activate Snf1 in vivo. However, deletion of the PAK1 gene suppresses many of the phenotypes associated with the deletion of the REG1 gene, providing genetic evidence that Pak1 activates Snf1 in vivo. The closest mammalian homologue of yeast Pak1 kinase, calcium-calmodulin-dependent protein kinase kinase beta, may play a similar role in mammalian nutrient stress signaling.
Mol Cell Biol 2003 Jun
PMID:Yeast Pak1 kinase associates with and activates Snf1. 1274 92

We have expressed in yeast the different subunits of AMP-activated protein kinase (AMPK) and, by using the two-hybrid system, we have found a glucose-regulated interaction between alpha 2 catalytic and gamma 1 regulatory subunits. This regulation was not affected by known regulators of the corresponding yeast orthologue, the SNF1 complex, such as Reg1 or Hxk2, but it was affected by deletion of regulatory subunits of yeast type 2A protein phosphatase (PP2A) complex. We have also found that Tpd3 and PR65 alpha, the corresponding yeast and mammalian A subunits of PP2A, interacted with AMPK alpha 2 both in yeast and mammals, respectively. This interaction occurred only through the regulatory domain of this subunit. These results suggested a direct involvement of PP2A complex in regulating the interaction between AMPK alpha 2 and gamma 1 in a glucose-dependent manner.
J Mol Biol 2003 Oct 10
PMID:Glucose and type 2A protein phosphatase regulate the interaction between catalytic and regulatory subunits of AMP-activated protein kinase. 1451 53

The yeast Snf1 kinase and its mammalian ortholog, AMP-activated protein kinase (AMPK), regulate responses to metabolic stress. Previous studies identified a glycogen-binding domain in the AMPK beta1 subunit, and the sequence is conserved in the Snf1 kinase beta subunits Gal83 and Sip2. Here we use genetic analysis to assess the role of this domain in vivo. Alteration of Gal83 at residues that are important for glycogen binding of AMPK beta1 abolished glycogen binding in vitro and caused diverse phenotypes in vivo. Various Snf1/Gal83-dependent processes were upregulated, including glycogen accumulation, expression of RNAs encoding glycogen synthase, haploid invasive growth, the transcriptional activator function of Sip4, and activation of the carbon source-responsive promoter element. Moreover, the glycogen-binding domain mutations conferred transcriptional regulatory phenotypes even in the absence of glycogen, as determined by analysis of a mutant strain lacking glycogen synthase. Thus, mutation of the glycogen-binding domain of Gal83 positively affects Snf1/Gal83 kinase function by a mechanism that is independent of glycogen binding.
Mol Cell Biol 2004 Jan
PMID:Mutations in the gal83 glycogen-binding domain activate the snf1/gal83 kinase pathway by a glycogen-independent mechanism. 1467 68

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.
Expert Rev Mol Diagn 2004 Jan
PMID:Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing. 1471 53

The Snf1/AMP-activated protein kinase family has diverse roles in cellular responses to metabolic stress. In Saccharomyces cerevisiae, Snf1 protein kinase has three isoforms of the beta subunit that confer versatility on the kinase and that exhibit distinct patterns of subcellular localization. The Sip1 beta subunit resides in the cytosol in glucose-grown cells and relocalizes to the vacuolar membrane in response to carbon stress. We show that translation of Sip1 initiates at the second ATG of the open reading frame, yielding a potential site for N myristoylation, and that mutation of the critical glycine abolishes relocalization. We further show that the cyclic AMP-dependent protein kinase (protein kinase A [PKA]) pathway maintains the cytoplasmic localization of Sip1 in glucose-grown cells. The Snf1 catalytic subunit also exhibits aberrant localization to the vacuolar membrane in PKA-deficient cells, indicating that PKA regulates the localization of Snf1-Sip1 protein kinase. These findings establish a novel mechanism of regulation of Snf1 protein kinase by the PKA pathway.
Mol Cell Biol 2004 Mar
PMID:Cyclic AMP-dependent protein kinase regulates the subcellular localization of Snf1-Sip1 protein kinase. 1496 66


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