DOCSLIB.ORG

The Role of GSK3 in Metabolic Pathway Perturbations in Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of GSK3 in Metabolic Pathway Perturbations in Cancer BBA - Molecular Cell Research 1868 (2021) 119059 Contents lists available at ScienceDirect BBA - Molecular Cell Research journal homepage: www.elsevier.com/locate/bbamcr Review ☆ The role of GSK3 in metabolic pathway perturbations in cancer David Papadopoli a,b,*, Michael Pollak a,b,c, Ivan Topisirovic a,b,c,d a Lady Davis Institute for Medical Research, 3755 Chemin de la Cote-Sainte-Catherine,^ Montr´eal, QC H3T 1E2, Canada b Gerald Bronfman Department of Oncology, McGill University, 5100 Maisonneuve Blvd West, Montr´eal, QC H4A 3T2, Canada c Department of Medicine, Division of Experimental Medicine, McGill University, 1001 D´ecarie Blvd, Montr´eal, QC H4A 3J1, Canada d Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montr´eal, QC H3G 1Y6, Canada ARTICLE INFO ABSTRACT Keywords: Malignant transformation and tumor progression are accompanied by significant perturbations in metabolic GSK3 programs. As such, cancer cells support high ATP turnover to construct the building blocks needed to fuel Cancer neoplastic growth. The coordination of metabolic networks in malignant cells is dependent on the collaboration mTOR with cellular signaling pathways. Glycogen synthase kinase 3 (GSK3) lies at the convergence of several signaling AMPK axes, including the PI3K/AKT/mTOR, AMPK, and Wnt pathways, which influence cancer initiation, progression Metabolism and therapeutic responses. Accordingly, GSK3 modulates metabolic processes, including protein and lipid syn­ thesis, glucose and mitochondrial metabolism, as well as autophagy. In this review, we highlight current knowledge of the role of GSK3 in metabolic perturbations in cancer. 1. Introduction their structural similarities, the GSK3 isoforms are non-redundant [6]. Homozygous knockout mice of the more widely studied isoform, GSK3B, Cellular proliferation and survival require coordination of multifac­ are not viable due to, at least in part, induction of apoptosis in the liver eted signaling events. Glycogen synthase kinase 3 (GSK3) is a serine/ [12]. However, GSK3A knockout mice are viable but exhibit impaired threonine kinase with a large number of established and putative sub­ spermatogenesis [13]. In addition, GSK3A knockouts demonstrate strates [1,2] that are implicated in various cellular functions [3]. elevated insulin sensitivity and increased hepatic glycogen storage [14]. Although originally discovered as a regulator of glycogen synthase, In mammals, GSK3α is inhibited by phosphorylation at Ser21 and acti­ GSK3 is involved in modulating numerous processes, including meta­ vated by Tyr279 phosphorylation, while phosphorylation at Ser9 and bolism, proliferation, apoptosis, autophagy, development, and differ­ Tyr216 signify suppression and activation of GSK3β, respectively [15]. entiation [4]. Phosphorylation of a target by GSK3 is often preceded by GSK3α and GSK3β are both inhibited by phosphorylation by protein priming kinases, such as protein kinase A (PKA), protein kinase C (PKC), kinase B (PKB/AKT) [16], 90-kDa ribosomal S6 kinase (RSK) [17–19], protein kinases CK1 and CK2, and cyclin-dependent kinase-5 (CDK-5) 70-kDa ribosomal S6 kinase (S6K) [17,18], and PKA [15]. In contrast, [5,6]. GSK3-mediated phosphorylation frequently leads to inactivation PKC selectively inhibits GSK3β, while not appearing to effect GSK3α and proteasomal degradation of its targets [4]. Based on its broad [20]. The activity of GSK3 is also positively regulated through dephos­ function, GSK3 has been linked to several pathologies including cancer, phorylation of its inhibitory sites. The protein phosphatase 1 (PP1) de­ diabetes, mood disorders, atherosclerosis, Alzheimer's disease, and phosphorylates Ser9 and activates GSK3β [21–23]. In turn, GSK3 Parkinson's disease, among others [4,7,8]. GSK3 exists in two isoforms collaborates with CK2 to inactivate protein phosphatase inhibitor-2 GSK3α and GSK3β (encoded by GSK3A and GSK3B genes) [9]. Although (PPI2), a negative regulator of PP1 [23–26]. Thus, GSK3 attenuates GSK3 isoforms have unique N- and C-terminal regions, they share a the inhibition of PP1, thereby enhancing its own activity through a highly conserved catalytic domain (98%) [4,10]. Both isoforms are positive feedback loop [27]. In addition, CK2 and GSK3β also cooperate ubiquitously expressed, with highest expression in the brain and lowest to phosphorylate the phosphatase and tensin homologue (PTEN) in the pancreas, according to the Human Protein Atlas [11]. Despite [28,29], although the effect is unclear [30]. ☆ This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus. * Corresponding author at: Lady Davis Institute for Medical Research, 3755 Chemin de la Cote-Sainte-Catherine,^ Montr´eal, QC H3T 1E2, Canada. E-mail address: [email protected] (D. Papadopoli). https://doi.org/10.1016/j.bbamcr.2021.119059 Received 16 February 2021; Received in revised form 16 April 2021; Accepted 17 April 2021 Available online 12 May 2021 0167-4889/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). D. Papadopoli et al. BBA - Molecular Cell Research 1868 (2021) 119059 Aside from phosphorylation, the activity of GSK3 is also dependent the translation of nuclear-encoded mRNAs encoding mitochondrial on its localization within cells. For instance, GSK3 targets transcription factors through inhibition of 4E-BPs [55]. The mTORC1/4E-BP axis also factors, such as c-MYC [31], SNAIL [32], and β-catenin [33], which regulates mitochondrial dynamics through MTFP1 [56]. In contrast, translocate from the cytosol to the nucleus. GSK3β was also suggested to mTORC2 is involved in the regulation of cytoskeleton and cell migration localize to mitochondria under stress, including ischemia/reperfusion in through PKCα [57]. mTORC2 also phosphorylates the hydrophobic the rat heart [34]. Conversely, GSK3α was reported to localize in nu- motif (surrounding Ser473 in humans) of AKT, which controls both cleus, but not in mitochondria [35]. Collectively, these findings glucose and lipid metabolism [58–60], and directs signaling through the demonstrate distinct regulation and functional non-redundancy of GSK3 mitochondrial-associated ER membrane (MAM) to control mitochon- isoforms. drial physiology [58–61]. In addition, mTORC2 controls ion transport In light of its involvement with signaling pathways implicated in through serum and glucocorticoid-regulated kinase 1 (SGK1) [62]. Both cancer, it is not surprising that GSK3 plays a prominent role in neoplasia. AKT and SGK1 negatively regulate apoptosis through the inhibition of To this end, GSK3 isoforms appear to play a dual role in cancer, whereby forkhead box protein O1/O3A (FOX01/3A) [57]. As a result, the PI3K/ both tumor promoting and tumor suppressive effects of GSK3 have been AKT/mTOR signaling modulates several metabolic nodes required by reported [36]. For instance, high GSK3 expression is associated with cancer cells to meet their high proliferative demands and promote their reduced relapse-free survival in breast cancer and GSK3 inhibitors survival and proliferation. suppress breast tumor growth in pre-clinical models [37]. In contrast, mTOR signaling is tightly regulated under periods of energetic stress AKT-dependent inhibition of GSK3 leads to a de-repression of GSK3 which at least in part occurs through the AMP-activated protein kinase substrates such as SNAIL, thus promoting breast tumorigenesis and (AMPK), a heterotrimeric serine/threonine kinase that is activated in disease progression [38]. These and similar studies therefore suggest response to metabolic stress and inhibited when ATP levels are high that the outcome of aberrant GSK3 activity in neoplasia is likely the [63]. Specifically,AMPK is activated by high AMP/ADP and through the result of effects on multiple signaling pathways, which are distinctively phosphorylation of liver kinase B1 (LKB1), calmodulin-dependent pro- affected through genetic and environmental alterations found in tein kinase kinase β (CAMKKβ), or TGF-β-activated kinase 1 (TAK-1) different cancer types. While Duda et al. provide an overarching review [63]. AMPK is also regulated independently of adenylate charge, of differential GSK3 involvement across a variety of malignancies [36], whereby glucose deprivation via the loss of fructose-1,6-bisphosphate herein we will focus on the potential roles of GSK3 in metabolic (FBP) binding to aldolase, allows for the activation of AMPK through reprogramming in cancer. the recruitment of Axin-LKB1 complex to the aldolase/V-ATPase/ Ragulator complex on lysosomes [64]. Finally AMPK can be induced 2. GSK3: orcestrator of metabolic signaling pathways by ROS [65]. In general, AMPK promotes energy homeostasis by inhibiting ATP-consuming processes. It negatively regulates fatty acid 2.1. PI3K/AKT/mTOR and AMPK cross-talk biosynthesis through inhibition of acetyl-CoA carboxylase [66,67] and SREBP1 [68]. Due to high energy demand, protein synthesis is also GSK3 is a key effector of PI3K/AKT signaling [39]. Class I phos- heavily restricted under periods of metabolic stress. AMPK inhibits phatidylinositol 3-kinases (PI3K) convert phosphoinositol 4,5-bisphos- mRNA translation by suppressing mTORC1 signaling through the phate (PIP2) to phosphoinositol 3,4,5-bisphosphate (PIP3) and are phosphorylation of TSC2 [69] and the regulatory-associated
Load more

Recommended publications
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • Aberrant Modulation of Ribosomal Protein S6 Phosphorylation Confers Acquired Resistance to MAPK Pathway Inhibitors in BRAF-Mutant Melanoma
    www.nature.com/aps ARTICLE Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma Ming-zhao Gao1,2, Hong-bin Wang1,2, Xiang-ling Chen1,2, Wen-ting Cao1,LiFu1, Yun Li1, Hai-tian Quan1,2, Cheng-ying Xie1,2 and Li-guang Lou1,2 BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signaling in parental cells, was switched to mTOR/ P70S6K signaling in resistant cells. Furthermore, mTOR inhibitors alone overcame acquired resistance and rescued the sensitivity of the resistant cells when combined with BRAF/MEK inhibitors.
    [Show full text]
  • Human Melanoma Cells Resistant to MAPK Inhibitors Can Be Effectively Targeted by Inhibition of the P90 Ribosomal S6 Kinase
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 22), pp: 35761-35775 Research Paper Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase Corinna Kosnopfel1, Tobias Sinnberg1, Birgit Sauer1, Heike Niessner1, Anja Schmitt2, Elena Makino1, Andrea Forschner1, Stephan Hailfinger2, Claus Garbe1, Birgit Schittek1 1Division of Dermatooncology, Department of Dermatology, University of Tübingen, Tübingen, Germany 2Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany Correspondence to: Birgit Schittek, email: [email protected] Keywords: melanoma, MAPK inhibition, therapy resistance, p90 ribosomal S6 kinase, YB-1 Received: January 18, 2017 Accepted: March 06, 2017 Published: March 15, 2017 Copyright: Kosnopfel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy. Here, we can show that RSK activity is significantly increased in human melanoma cells with acquired resistance to the BRAFV600E/K inhibitor vemurafenib. Interestingly, inhibition of RSK signalling markedly impairs the viability of vemurafenib resistant melanoma cells and is effective both in two-dimensional and in three-dimensional culture systems, especially in a chronic, long-term application.
    [Show full text]
  • The Role of the S6K2 Splice Isoform in Mtor/S6K Signalling and Cellular Functions
    The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions Olena Myronova A thesis submitted to the University College London in fulfilment with the requirements for the degree of Doctor of Philosophy London, November 2015 Research Department of Structural and Molecular Biology Division of Biosciences University College London Gower Street London, WC1E 6BT United Kingdom Ludwig Institute for Cancer Research 666 Third Avenue, 28th floor New York, N.Y. 10017 USA The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions 1 Declaration I, Olena Myronova, declare that all the work presented in this thesis is the result of my own work. The work presented here does not constitute part of any other thesis. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. The work here in was carried out while I was a graduate research student at University College London, Research Department of Structural and Molecular Biology under the supervision of Professor Ivan Gout. Olena Myronova The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions 2 Abstract Ribosomal S6 kinase (S6K) is a member of the AGC family of serine/threonine protein kinases and plays a key role in diverse cellular processes, including cell growth, survival and metabolism. Activation of S6K by growth factors, amino acids, energy levels and hypoxia is mediated by the mTOR and PI3K signalling pathways. Dysregulation of S6K activity has been implicated in a number of human pathologies, including cancer, diabetes, obesity and ageing.
    [Show full text]
  • Glycogen Synthase Kinase-3 Is Activated in Neuronal Cells by G 12
    The Journal of Neuroscience, August 15, 2002, 22(16):6863–6875 Glycogen Synthase Kinase-3 Is Activated in Neuronal Cells by G␣ ␣ 12 and G 13 by Rho-Independent and Rho-Dependent Mechanisms C. Laura Sayas, Jesu´ s Avila, and Francisco Wandosell Centro de Biologı´a Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Cientı´ficas, Universidad Auto´ noma de Madrid, Cantoblanco, Madrid 28049, Spain ␣ ␣ ␣ ␣ Glycogen synthase kinase-3 (GSK-3) was generally considered tively active G 12 (G 12QL) and G 13 (G 13QL) in Neuro2a cells a constitutively active enzyme, only regulated by inhibition. induces upregulation of GSK-3 activity. Furthermore, overex- Here we describe that GSK-3 is activated by lysophosphatidic pression of constitutively active RhoA (RhoAV14) also activates ␣ acid (LPA) during neurite retraction in rat cerebellar granule GSK-3 However, the activation of GSK-3 by G 13 is blocked by neurons. GSK-3 activation correlates with an increase in GSK-3 coexpression with C3 transferase, whereas C3 does not block ␣ tyrosine phosphorylation. In addition, LPA induces a GSK-3- GSK-3 activation by G 12. Thus, we demonstrate that GSK-3 is ␣ ␣ mediated hyperphosphorylation of the microtubule-associated activated by both G 12 and G 13 in neuronal cells. However, ␣ protein tau. Inhibition of GSK-3 by lithium partially blocks neu- GSK-3 activation by G 13 is Rho-mediated, whereas GSK-3 ␣ rite retraction, indicating that GSK-3 activation is important but activation by G 12 is Rho-independent. The results presented not essential for the neurite retraction progress. GSK-3 activa- here imply the existence of a previously unknown mechanism of ␣ tion by LPA in cerebellar granule neurons is neither downstream GSK-3 activation by G 12/13 subunits.
    [Show full text]
  • Extracellular Receptor Kinase and Camp Response Element Binding Protein Activation in the Neonatal Rat Heart After Perinatal Cocaine Exposure
    0031-3998/04/5606-0947 PEDIATRIC RESEARCH Vol. 56, No. 6, 2004 Copyright © 2004 International Pediatric Research Foundation, Inc. Printed in U.S.A. Extracellular Receptor Kinase and cAMP Response Element Binding Protein Activation in the Neonatal Rat Heart after Perinatal Cocaine Exposure LENA S. SUN AND AARON QUAMINA Department of Anesthesiology [L.S.S., A.Q.] and Pediatrics [L.S.S.], College of Physicians & Surgeons, Columbia University, New York, NY 10032 ABSTRACT Prenatal exposure to cocaine has been shown to induce an and phospho-RSK. We assessed the interaction of RSK with increase in the myocardial expression and activation of the CREB or CREB-binding protein by performing co-immunopre- cAMP response binding protein (CREB), a transcriptional factor cipitation experiments. We found that perinatal cocaine exposure that has been shown to regulate gene expression. Several differ- increased both phospho-ERK and phospho-RSK expression, in- ent kinases, including protein kinase A, calcium calmodulin dicative of an increased activity of these two enzymes. Further- kinase II, and mitogen-activated protein kinase can induce phos- more, we demonstrated that phospho-RSK was immunoprecipi- phorylation of CREB at serine 133, a necessary step for CREB tated with CREB in all neonatal cardiac nuclei and that the activation. We examined whether the mitogen-activated protein greatest interaction was found in day 7 hearts after perinatal kinase–extracellular receptor kinase (ERK) pathway may be cocaine exposure. Our results thus illustrate that the ERK-RSK involved in mediating the serine 133 CREB phosphorylation in pathway was active in the postnatal rat heart at 1 and7dofage cardiac nuclei after perinatal cocaine exposure.
    [Show full text]
  • Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase
    cells Review Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase Jaroslav Kalous *, Denisa Jansová and Andrej Šušor Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Rumburska 89, 27721 Libechov, Czech Republic; [email protected] (D.J.); [email protected] (A.Š.) * Correspondence: [email protected] Received: 28 April 2020; Accepted: 24 June 2020; Published: 27 June 2020 Abstract: Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of CDK1 in the initiation and elongation steps of protein synthesis in the cell. During its activation, CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1 to optimize temporal synthesis of proteins to sustain the division-related processes: mitosis and cytokinesis. Keywords: CDK1; 4E-BP1; mTOR; mRNA; translation; M-phase 1. Introduction 1.1. Cyclin Dependent Kinase 1 (CDK1) Is a Subunit of the M Phase-Promoting Factor (MPF) CDK1, a serine/threonine kinase, is a catalytic subunit of the M phase-promoting factor (MPF) complex which is essential for cell cycle control during the G1-S and G2-M phase transitions of eukaryotic cells.
    [Show full text]
  • The P90 RSK Family Members: Common Functions and Isoform Specificity
    Published OnlineFirst August 22, 2013; DOI: 10.1158/0008-5472.CAN-12-4448 Cancer Review Research The p90 RSK Family Members: Common Functions and Isoform Specificity Romain Lara, Michael J. Seckl, and Olivier E. Pardo Abstract The p90 ribosomal S6 kinases (RSK) are implicated in various cellular processes, including cell proliferation, survival, migration, and invasion. In cancer, RSKs modulate cell transformation, tumorigenesis, and metastasis. Indeed, changes in the expression of RSK isoforms have been reported in several malignancies, including breast, prostate, and lung cancers. Four RSK isoforms have been identified in humans on the basis of their high degree of sequence homology. Although this similarity suggests some functional redundancy between these proteins, an increasing body of evidence supports the existence of isoform-based specificity among RSKs in mediating particular cellular processes. This review briefly presents the similarities between RSK family members before focusing on the specific function of each of the isoforms and their involvement in cancer progression. Cancer Res; 73(17); 1–8. Ó2013 AACR. Introduction subsequently cloned throughout the Metazoan kingdom (2). The extracellular signal–regulated kinase (ERK)1/2 pathway The genomic analysis of several cancer types suggests that fi is involved in key cellular processes, including cell prolifera- these genes are not frequently ampli ed or mutated, with some tion, differentiation, survival, metabolism, and migration. notable exceptions (e.g., in the case of hepatocellular carcino- More than 30% of all human cancers harbor mutations within ma; ref. 6). Table 1 summarizes reported genetic changes in this pathway, mostly resulting in gain of function and conse- RSK genes.
    [Show full text]
  • Chem331 Glycogen Metabolism
    Glycogen metabolism Glycogen review - 1,4 and 1,6 α-glycosidic links ~ every 10 sugars are branched - open helix with many non-reducing ends. Effective storage of glucose Glucose storage Liver glycogen 4.0% 72 g Muscle glycogen 0.7% 245 g Blood Glucose 0.1% 10 g Large amount of water associated with glycogen - 0.5% of total weight Glycogen stored in granules in cytosol w/proteins for synthesis, degradation and control There are very different means of control of glycogen metabolism between liver and muscle Glycogen biosynthetic and degradative cycle Two different pathways - which do not share enzymes like glycolysis and gluconeogenesis glucose -> glycogen glycogenesis - biosynthetic glycogen -> glucose 1-P glycogenolysis - breakdown Evidence for two paths - Patients lacking phosphorylase can still synthesize glycogen - hormonal regulation of both directions Glycogenolysis (glycogen breakdown)- Glycogen Phosphorylase glycogen (n) + Pi -> glucose 1-p + glycogen (n-1) • Enzyme binds and cleaves glycogen into monomers at the end of the polymer (reducing ends of glycogen) • Dimmer interacting at the N-terminus. • rate limiting - controlled step in glycogen breakdown • glycogen phosphorylase - cleavage of 1,4 α glycosidic bond by Pi NOT H2O • Energy of phosphorolysis vs. hydrolysis -low standard state free energy change -transfer potential -driven by Pi concentration -Hydrolysis would require additional step s/ cost of ATP - Think of the difference between adding a phosphate group with hydrolysis • phosphorylation locks glucose in cell (imp. for muscle) • Phosphorylase binds glycogen at storage site and the catalytic site is 4 to 5 glucose residues away from the catalytic site. • Phosphorylase removes 1 residue at a time from glycogen until 4 glucose residues away on either side of 1,6 branch point – stericaly hindered by glycogen storage site • Cleaves without releasing at storage site • general acid/base catalysts • Inorganic phosphate attacks the terminal glucose residue passing through an oxonium ion intermediate.
    [Show full text]
  • The Origins of Protein Phosphorylation
    historical perspective The origins of protein phosphorylation Philip Cohen The reversible phosphorylation of proteins is central to the regulation of most aspects of cell func- tion but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a per- sonal view of the key findings that have helped to shape the field as we know it today. he days when protein phosphorylation was an abstruse backwater, best talked Tabout between consenting adults in private, are over. My colleagues no longer cringe on hearing that “phosphorylase kinase phosphorylates phosphorylase” and their eyes no longer glaze over when a “”kinase kinase kinase” is mentioned. This is because protein phosphorylation has gradu- ally become an integral part of all the sys- tems they are studying themselves. Indeed it would be difficult to find anyone today who would disagree with the statement that “the reversible phosphorylation of proteins regu- lates nearly every aspect of cell life”. Phosphorylation and dephosphorylation, catalysed by protein kinases and protein phosphatases, can modify the function of a protein in almost every conceivable way; for Carl and Gerty Cori, the 1947 Nobel Laureates. Picture: Science Photo Library. example by increasing or decreasing its bio- logical activity, by stabilizing it or marking it for destruction, by facilitating or inhibiting movement between subcellular compart- so long before its general significance liver enzyme that catalysed the phosphory- ments, or by initiating or disrupting pro- was appreciated? lation of casein3. Soon after, Fischer and tein–protein interactions.
    [Show full text]
  • AMP-Activated Protein Kinase: the Current Landscape for Drug Development
    REVIEWS AMP-activated protein kinase: the current landscape for drug development Gregory R. Steinberg 1* and David Carling2 Abstract | Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elicit beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Cardiovascular disease Dramatic improvements in health care coupled with identifying a unifying mechanism that could link these (CVD). A term encompassing an increased standard of living, including better nutri- changes to multiple branches of metabolism followed diseases affecting the heart tion and education, have led to a remarkable increase in the discovery that the AMP-activated protein kinase or circulatory system. human lifespan1. Importantly, the number of years spent (AMPK) provided a common regulatory mechanism in good health is also increasing2. Despite these positive for inhibiting both cholesterol (through phosphoryla- Non-alcoholic fatty liver disease developments, there are substantial risks that challenge tion of HMG-CoA reductase (HMGR)) and fatty acid (NAFLD). A very common continued improvements in human health. Perhaps the (through phosphorylation of acetyl-CoA carboxylase disease in humans in which greatest threat to future health is a chronic energy imbal- (ACC)) synthesis8 (BOx 1).
    [Show full text]
  • Glycogenosis Due to Liver and Muscle Phosphorylase Kinase Deficiency
    Pediat. Res. 15: 299-303 (198 1) genetics muscle glycogenosis phosphorylase kinase deficiency liver Glycogenosis Due to Liver and Muscle Phosphorylase Kinase Deficiency N. BASHAN. T. C. IANCU. A. LERNER. D. FRASER, R. POTASHNIK. AND S. W. MOSES'"' Pediatric Research Laborarorv. Soroka Medical Center. Iaculr~of Health Sciences. Ben-Gurion Universi!,' of Negev. Beer-Sheva, and Department of Pediatrics. Carmel Hospiral. Huifa. Israel Summary hepatomegaly. The family history disclosed that two sisters were similarly affected, whereas one older brother was apparently A four-year-old Israeli Arab boy was found to have glycogen healthy. accumulation in both liver and muscle without clinical symptoms. Past history was unremarkable. The patient's height was below Liver phosphorylase kinase (PK) activity was 20% of normal, the third percentile for his age in contrast to a normal weight. He resulting in undetectable activity of phosphorylase a. Muscle PK had a doll face and a protuberant abdomen. The liver was palpable activity was about 25% of normal, resulting in a marked decrease 9 cm below the costal margin. Slight muscular hypotonia and of phosphorylase a activity. weakness were noticeable with normal tendon reflexes. He had Two sisters showed a similar pattern, whereas one brother had slightly abnormal liver function tests. a fasting blood sugar of 72 normal PK activity. The patient's liver protein kinase activity was mg %, a normal glucagon test. and no lactic acidemia or uricemia normal. Addition of exogenous protein kinase did not affect PK but slight lipidemia. Electronmicroscopic studies of a liver biopsy activity, whereas exogenous PK restored phosphorylase activity revealed marked deposition of glycogen.
    [Show full text]