Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to their ligand-mediated activation, nuclear receptor activity is finely tuned by their phosphorylation status. PPARs are phosphorylated by several kinases (PKA, PKC, MAPKs, and AMPK), which affect their activity in a ligand-dependent or -independent manner according to the isoform and cellular context. Molecular consequences are multiple, including changes in ligand affinity, DNA binding, recruitment of transcriptional cofactors, proteasome degradation... Finally, the physiological relevance of PPAR phosphorylation is discussed.
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PMID:Phosphorylation of PPARs: from molecular characterization to physiological relevance. 1573 34

Deletion mutations of mitochondrial DNA (mtDNA) accumulate somatically on a cell-by-cell basis with age, resulting in decreased cell function in muscle and substantia nigra. In osteosarcoma cells deletions incapacitate mitochondria and induce the autophagic transcript ATG12, which is involved in an early step of the mammalian autophagy pathway. We discuss here which consequences of mtDNA deletions could induce ATG12, and provide two new pieces of data. Our previous studies demonstrated that mtDNA deletions decreased mitochondrial ATP production and proteasomal function, induced the AMPK transcript (likely as a consequence of bioenergetic depletion), and decreased the intracellular concentration of 20 amino acids (possibly as a consequence of decreased proteasomal activity). Deletions eliminate essential tRNAs for mitochondrial protein synthesis, as well as essential components of mitochondrial multisubunit enzymes; therefore, the increased level of ATG12 could result from decreased bioenergetic function, increased oxidative damage, or decreased mitochondrial protein synthesis. However, the bioenergetic inhibitor rotenone does not induce ATG12. We show here that chloramphenicol, which inhibits mitochondrial protein synthesis, induces ATG12, and that mtDNA deletions result in an increased burden of oxidatively damaged protein. Thus, mtDNA deletions could induce ATG12 through a mechanism such as the following: deletions > mitochondrial protein synthesis inhibition or ROS > proteasome inhibition > amino acid depletion > ATG12.
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PMID:Mitochondrial DNA deletions and chloramphenicol treatment stimulate the autophagic transcript ATG12. 1715 91

LKB1, a tumor suppressor gene mutated in the Peutz-Jeghers syndrome, encodes a serine/threonine protein kinase. Recent biochemical studies have shown that LKB1 activates 14 AMP-activated protein kinase-related kinases including MARKs (microtubule-associated protein/microtubule affinity-regulating kinases) that regulate microtubule dynamics. Here we show in vitro that LKB1 phosphorylates and activates MARK2, which in turn phosphorylates microtubule-associated protein Tau at the KXGS motif and suppresses tubulin polymerization. In cells, forced expression of LKB1 suppresses microtubule regrowth, whereas LKB1 knockdown accelerates it. We further show that the phosphorylation of Tau by the LKB1-MARK signaling triggers proteasome-mediated degradation of Tau. These results indicate that LKB1 is involved in the regulation of microtubule dynamics through the activation of MARKs.
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PMID:Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling. 1757 48

In skeletal muscle, AMP-activated protein kinase (AMPK) is a metabolic master switch regulating glucose and lipid metabolism. Recently, AMPK has been implicated in the control of protein synthesis in skeletal muscle, but the effect of AMPK activation on myofibrillar protein degradation has yet to be elucidated. The present study was designed to examine the effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR)-induced AMPK signaling on effector mechanisms of myofibrillar protein degradation and the expression of atrophy-related genes (atrogin-1/MAFbx, MuRF1, proteasome C2 subunit, calpains, cathepsin B, and caspase-3) in C2C12 myotubes. AICAR stimulated myofibrillar protein degradation (as measured by N(tau)-methylhistidine release), while also increasing the levels of atrogin-1/MAFbx and MuRF1 mRNA, but the expression of other atrophy-related genes was not enhanced by AICAR treatment in C2C12 myotubes. AICAR also stimulated the level of FOXO transcription factors mRNA and protein in C2C12 myotubes. These results indicate that activation of AMPK stimulates myofibrillar protein degradation through the expression of atrogin-1/MAFbx and MuRF1 by increasing FOXO transcription factors in skeletal muscles.
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PMID:AMPK activation stimulates myofibrillar protein degradation and expression of atrophy-related ubiquitin ligases by increasing FOXO transcription factors in C2C12 myotubes. 1761 26

In this work we present evidence that A769662, a novel activator of AMP-activated protein kinase (AMPK), is able to inhibit the function of the 26S proteasome by an AMPK-independent mechanism. Contrary to the mechanism of action of most proteasome inhibitors, A769662 does not affect the proteolytic activities of the 20S core subunit, defining in this way a novel mechanism of inhibition of 26S proteasome activity. Inhibition of proteasome activity by A769662 is reversible and leads to an arrest of cell cycle progression. These side effects of this new activator of AMPK should be taken into account when this compound is used as an alternative activator of the kinase.
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PMID:A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. 1859 84

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
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PMID:Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation. 1939 13

The death receptor Fas (APO-1/CD95) induces apoptosis in many tissues upon cross-linking by its ligand (FasL), but a number of cancer cells exhibit resistance to such apoptosis. Indeed, resistance to apoptosis seems to be one of the hallmarks of cancer, and therefore, it is clinically important to understand the underlying mechanisms by which cancer cells acquire such resistance. In the present study, we demonstrate that Fas signaling in DU145 human prostate cancer cells leads to rapid activation of AMP-activated protein kinase (AMPK), which plays a major role in adaptive responses to ATP-depleting conditions; prostate cancer is resistant to Fas-mediated apoptosis despite high levels of Fas surface expression and no mutation in the Fas gene. We further demonstrate that inhibition of AMPK sensitizes DU145 cells to Fas-induced apoptosis via enhancement of ubiquitination and consequent proteasome degradation of the apoptosis inhibitory protein c-FLIP. These findings thus reveal a novel anticancer property of AMPK inhibition and support the synergistic application of AMPK inhibition in cancer therapy to overcome Fas resistance.
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PMID:Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation. 1947 72

Mammalian AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine protein kinase that acts as a sensor of cellular energy status. It interacts with a great variety of different substrates leading to short-term (i.e. regulation of the activity of different enzymes by direct phosphorylation) and long-term effects (i.e. regulation of transcriptional activity of different transcription factors). In this work, we describe the use of the yeast two-hybrid technology to identify additional proteins that interact with the different subunits of AMPK. We have performed three yeast two-hybrid screenings of a human skeletal muscle cDNA library using three different baits: a constitutively active form of AMPKalpha2 (LexA-AMPKalpha2-T172D) co-expressed with AMPKgamma1, LexA-AMPKbeta2 and LexA-AMPKgamma3. Our results identify novel interaction partners of AMPK in human skeletal muscle. We also further characterize the interaction of AMPK with one of these novel interacting proteins, the non-ATPase subunit of the proteasome PSMD11. Our results indicate that AMPK is able to interact physically with this subunit and modify its phosphorylation status, supporting a possible role for AMPK in regulating proteasome function.
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PMID:Two-hybrid analysis identifies PSMD11, a non-ATPase subunit of the proteasome, as a novel interaction partner of AMP-activated protein kinase. 1961 15

Mitochondria are crucial organelles in the production of energy and in the control of signalling cascades. A machinery of pro-fusion and fission proteins regulates their morphology and subcellular localization. In muscle this results in an orderly pattern of intermyofibrillar and subsarcolemmal mitochondria. Muscular atrophy is a genetically controlled process involving the activation of the autophagy-lysosome and the ubiquitin-proteasome systems. Whether and how the mitochondria are involved in muscular atrophy is unknown. Here, we show that the mitochondria are removed through autophagy system and that changes in mitochondrial network occur in atrophying muscles. Expression of the fission machinery is per se sufficient to cause muscle wasting in adult animals, by triggering organelle dysfunction and AMPK activation. Conversely, inhibition of the mitochondrial fission inhibits muscle loss during fasting and after FoxO3 overexpression. Mitochondrial-dependent muscle atrophy requires AMPK activation as inhibition of AMPK restores muscle size in myofibres with altered mitochondria. Thus, disruption of the mitochondrial network is an essential amplificatory loop of the muscular atrophy programme.
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PMID:Mitochondrial fission and remodelling contributes to muscle atrophy. 2040 Sep 40

Lafora progressive myoclonus epilepsy is a fatal neurodegenerative disorder caused by defects in the function of at least two proteins: laforin, a dual-specificity protein phosphatase, and malin, an E3-ubiquitin ligase. In this study, we report that a functional laforin-malin complex promotes the ubiquitination of AMP-activated protein kinase (AMPK), a serine/threonine protein kinase that acts as a sensor of cellular energy status. This reaction occurs when any of the three AMPK subunits (alpha, beta, and gamma) are expressed individually in the cell, and it also occurs on AMPK beta when it is part of a heterotrimeric complex. We also report that the laforin-malin complex promotes the formation of K63-linked ubiquitin chains, which are not involved in proteasome degradation. On the contrary, this modification increases the steady-state levels of at least AMPK beta subunit, possibly because it leads to the accumulation of this protein into inclusion bodies. These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.
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PMID:The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. 2053 8


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