A5003779033- Glycogen Storage Diseases and Myoclonus
- Protein Kinase Regulation and GTPase Signaling
- Genetics and Neurodevelopmental Disorders
- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Muscle metabolism and nutrition
- Mitochondrial Function and Pathology
- Pancreatic function and diabetes
- Ion channel regulation and function
- Protein Tyrosine Phosphatases
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Muscle Physiology and Disorders
- Polyamine Metabolism and Applications
- Metabolism and Genetic Disorders
- Glycosylation and Glycoproteins Research
- Cardiomyopathy and Myosin Studies
- Phytase and its Applications
- Fungal and yeast genetics research
- Amino Acid Enzymes and Metabolism
- Neuroscience and Neuropharmacology Research
- Lipid metabolism and biosynthesis
- Enzyme Structure and Function
- Neurological disorders and treatments
- Wnt/β-catenin signaling in development and cancer
Indiana University – Purdue University Indianapolis
2013-2024
Indiana University School of Medicine
2013-2024
University of Kentucky
2019-2024
Indiana University
1982-2016
Hospital for Sick Children
2011
Duke Medical Center
1995-2005
University of Cincinnati
2002-2005
Harvard University
2005
Massachusetts General Hospital
2005
Indiana University Bloomington
1994-2000
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role energy homeostasis and has been proposed as therapeutic target multiple storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors this enzyme. Here, we report preclinical characterization MZ-101, small molecule that potently inhibits GYS1 vitro vivo without inhibiting GYS2, related isoform essential for synthesizing liver glycogen....
The enzyme glycogen synthase kinase-3 (GSK-3) has been implicated in the control of several metabolic enzymes and transcription factors response to extracellular signals. In past, considered be a protein Ser/Thr kinase although it was recently reported contain Tyr(P) (Hughes, K., Nikolakaki, E., Plyte, S. Totty, N. F., Woodgett, J. R. (1993) EMBO 12, 803-808). A cDNA encoding rabbit skeletal muscle GSK-3 beta cloned expressed Escherichia coli as an active kinase, with apparent M(r) 46,000,...
Microscopic screening of a collection cold-sensitive mutants Saccharomyces cerevisiae led to the identification new gene, CDC55, which appears be involved in morphogenetic events cell cycle. CDC55 maps between CDC43 and CHC1 on left arm chromosome VII. At restrictive temperature, original cdc55 mutant produces abnormally elongated buds displays delay or partial block septation and/or separation. A deletion phenotype like that isolate. Sequencing revealed it encodes protein about 60 kDa, as...
Increases in type 1 phosphatase (PP1) activity have been observed end stage human heart failure, but the role of this enzyme cardiac function is unknown.To elucidate functional significance increased PP1 activity, we generated models with (i) overexpression catalytic subunit murine hearts and (ii) ablation PP1-specific inhibitor.Overexpression (threefold) was associated depressed function, dilated cardiomyopathy, premature mortality, consistent failure.Ablation inhibitor moderate increases...
When mouse 30A5 preadipocytes are exposed to high glucose concentrations, acetyl-CoA carboxylase is induced through activation of promoter II the gene. Glucose treatment cells increases Sp1 binding two GC-rich response elements in II. We have investigated mechanism by which and transactivation cells. DNA mobility shift assays shown that nuclear extracts from glucose-treated exhibit increased activity. This increase activity not due glucose-mediated changes amount nucleus but an modifies so...
Abnormal calcium cycling, characteristic of experimental and human heart failure, is associated with impaired sarcoplasmic reticulum uptake activity. This reflects decreases in the cAMP-pathway signaling increases type 1 phosphatase The increased protein activity partially due to dephosphorylation inactivation its inhibitor-1, promoting phospholamban inhibition calcium-pump. Indeed, cardiac-specific expression a constitutively active inhibitor-1 results selective enhancement phosphorylation...
The ATP-Mg-dependent phosphoprotein phosphatase is believed to consist of a catalytic subunit and regulatory component identified as inhibitor-2. It was found in this study that isolated inhibitor-2 phosphorylated serine residues by casein kinase II at least 3 mol phosphate per while another protein kinase, F A/GSK-3, introduced no more than 0.3 exclusively threonine residues. Analysis tryptic digests high performance liquid chromatography indicated action resulted two major (peaks 1 2)...
Cyclin G2, together with cyclin G1 and I, defines a novel family expressed in terminally differentiated tissues including brain muscle. G2 expression is up-regulated as cells undergo cell cycle arrest or apoptosis response to inhibitory stimuli independent of p53 (Horne, M., Donaldson, K., Goolsby, G., Tran, D., Mulheisen, Hell, J. Wahl, A. (1997) <i>J. Biol. Chem.</i> 272, 12650–12661). We tested the hypothesis that may be negative regulator progression found ectopic induces formation...
Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. bodies, deposits abnormally branched, insoluble glycogen-like polymers, form neurons, muscle, liver, other tissues. Approximately half cases result from mutations EPM2A gene, which encodes laforin, member dual-specificity protein phosphatase family that additionally contains glycogen binding domain. The molecular basis for formation bodies completely unknown....
The functional specificity of type 1 protein phosphatases (PP1) depends on the associated regulatory/targeting and inhibitory subunits. To gain insights into mechanism PP1 regulation by inhibitor-2, an ancient intrinsically disordered regulator, we solved crystal structure complex to 2.5A resolution. Our studies show that, when complexed with PP1c, I-2 acquires three regions order: site 1, residues 12-17, binds adjacent a region recognized many regulators; 2, amino acids 44-56, interacts...
A calmodulin-dependent protein kinase has been extensively purified from rabbit liver by the criterion of its ability to phosphorylate muscle glycogen synthase.The enzyme bound phosphocellulose, DEAE-cellulose, and blue dextran-agarose.The also bound, in a Caz+-dependent manner, calmodulin-agarose affinity column.Expression activity required presence both calmodulin Ca", with half-maxim l activation occurring at approximately 80 n M calmodulin.Trifluoperazine, 50 p ~, completely inhibited...
DNA clones encoding the glycogen-binding (RG1) subunit of glycogen-associated protein phosphatase were isolated from rabbit skeletal muscle lambda gt11 cDNA libraries. Overlapping provided an open reading frame 3327 nucleotides that predicts a polypeptide 1109 amino acids with molecular weight 124,257. Northern hybridization RNA identified major mRNA transcript 7.5 kilobases present in skeletal, diaphragm, and cardiac muscle, but not brain, kidney, liver, lung. Southern analysis genomic...
Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as bodies, which accumulate neurons, muscle, liver, other tissues. Approximately half cases result from mutations EPM2A gene, encodes laforin, member dual specificity protein phosphatase family that able to release small amount covalent...
Lafora disease is the most common teenage-onset neurodegenerative disease, main form of progressive myoclonus epilepsy (PME), and one severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies overtakes small processes, mainly dendrites. Polyglucosan formation catalyzed by glycogen synthase, which activated through dephosphorylation glycogen-associated protein phosphatase-1 (PP1). Here we remove PTG, proteins that target PP1 to glycogen,...
Stbd1 is a protein of previously unknown function that most prevalent in liver and muscle, the major sites for storage energy reserve glycogen. The predicted to contain hydrophobic N terminus C-terminal CBM20 glycan binding domain. Here, we show binds glycogen vitro endogenous locates perinuclear compartments cultured mouse FL83B or Rat1 cells. When overexpressed COSM9 cells, concentrated at enlarged structures, co-localized with glycogen, late endosomal/lysosomal marker LAMP1 autophagy...
Approximately 90% of cases Lafora disease, a fatal teenage-onset progressive myoclonus epilepsy, are caused by mutations in either the EPM2A or EPM2B genes that encode, respectively, glycogen phosphatase called laforin and an E3 ubiquitin ligase malin. disease is characterized formation bodies, insoluble deposits containing poorly branched polyglucosan, many tissues including skeletal muscle, liver, brain. Disruption Epm2b gene mice resulted viable animals that, 3 months age, accumulated...
Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor that regulates genes in the de novo lipogenesis and glycolysis pathways. The levels of SREBP-1 are significantly elevated obese patients animal models obesity type 2 diabetes, vast number studies have implicated this as contributor to hepatic lipid accumulation insulin resistance. However, its role regulating carbohydrate metabolism poorly understood. Here we addressed whether needed for glucose homeostasis....
Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD intracellular accumulation insoluble polysaccharide deposits known as bodies (LBs) brain and other tissues. In mouse models, genetic reduction glycogen synthesis eliminates LB formation rescues neurological phenotype. Therefore, LBs have become therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused...
Abstract Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated neuronal formation central nervous system, but neither its involvement pathological nor tested. Here we report a form neuroglia signalling involving astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation Protein Targeting to Glycogen (PTG)...
Phosphorylation of G-protein-coupled receptors plays an important role in regulating their function. In this study the receptor phosphatase (GRP) capable dephosphorylating kinase-phosphorylated is described. The GRP activity bovine brain a latent oligomeric form protein type 2A (PP-2A) exclusively associated with particulate fraction. observed only when assayed presence protamine or phosphatase-containing fractions are subjected to freeze/thaw treatment under reducing conditions. Consistent...
Association of the catalytic subunit (C2) with a variety regulatory subunits is believed to modulate activity and specificity protein phosphatase 2A (PP2A). In this study we report cloning expression new family B-subunit, B′, associated PP2A0 form. Polymerase chain reactions cDNA library screening have identified at least seven isotypes, designated α, β1, β2, β3, β4, γ, δ. The different β subtypes appear be generated by alternative splicing. deduced amino acid sequences β4 γ isoforms predict...