scholarly journals AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1

2020 ◽  
Vol 477 (12) ◽  
pp. 2237-2248
Author(s):  
Eri Matsumoto ◽  
Kaho Akiyama ◽  
Takuya Saito ◽  
Yu Matsumoto ◽  
Ken-Ichi Kobayashi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Mrna Splicing ◽  
Splicing Factor ◽  
Rna Recognition Motif ◽  
Rna Sequences ◽  
Macrophage Stimulating Protein ◽  
Protein Receptor ◽  
Amp Activated Protein Kinase ◽  
Splicing Factor 1

AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic processes and activating catabolic processes. Recent studies have demonstrated that metformin, which is an AMPK activator, modifies alternative precursor mRNA (pre-mRNA) splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In the present study, we identified the splicing factor serine/arginine-rich splicing factor 1 (SRSF1) as a novel AMPK substrate. AMPK directly phosphorylated SRSF1 at Ser133 in an RNA recognition motif. Ser133 phosphorylation suppressed the interaction between SRSF1 and specific RNA sequences without altering the subcellular localization of SRSF1. Moreover, AMPK regulated the SRSF1-mediated alternative pre-mRNA splicing of Ron, which is a macrophage-stimulating protein receptor, by suppressing its interaction with exon 12 of Ron pre-mRNA. The findings of this study revealed that the AMPK-dependent phosphorylation of SRSF1 at Ser133 inhibited the ability of SRSF1 to bind RNA and regulated alternative pre-mRNA splicing.

scholarly journals Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

2007 ◽  
Vol 192 (3) ◽  
pp. 605-614 ◽  
Author(s):  
Fang Cai ◽  
Armen V Gyulkhandanyan ◽  
Michael B Wheeler ◽  
Denise D Belsham
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glucose Sensing ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

Exercise and MEF2–HDAC interactions

2007 ◽  
Vol 32 (5) ◽  
pp. 852-856 ◽  
Author(s):  
Sean L. McGee
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Nuclear Export ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Positive Health ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase ◽  
Body Energy ◽  
Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

scholarly journals Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK)

2018 ◽  
Vol 293 (44) ◽  
pp. 16994-17007 ◽  
Author(s):  
Xin Gu ◽  
Michael D. Bridges ◽  
Yan Yan ◽  
Parker W. de Waal ◽  
X. Edward Zhou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Kinase Domain ◽  
Carbohydrate Binding ◽  
Conformational Heterogeneity ◽  
Α Subunit ◽  
Distance Distributions ◽  
Double Electron Electron Resonance ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the α-subunit and the carbohydrate-binding module (CBM) in the β-subunit. Here, using double electron–electron resonance (DEER) spectroscopy, we demonstrate that the CBM–KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD–CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD–CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals.

scholarly journals AMP-activated protein kinase pathway and bone metabolism

2011 ◽  
Vol 212 (3) ◽  
pp. 277-290 ◽  
Author(s):  
J Jeyabalan ◽  
M Shah ◽  
B Viollet ◽  
C Chenu
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Bone Cells ◽  
Peripheral Tissues ◽  
Ampk Signaling ◽  
Obesity And Diabetes ◽  
Regulate Food Intake ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formationin vitroand the deletion of α or β subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

scholarly journals AMP-activated Protein Kinase Impairs Endothelial Actin Cytoskeleton Assembly by Phosphorylating Vasodilator-stimulated Phosphoprotein

2006 ◽  
Vol 282 (7) ◽  
pp. 4601-4612 ◽  
Author(s):  
Constanze Blume ◽  
Peter M. Benz ◽  
Ulrich Walter ◽  
Joohun Ha ◽  
Bruce E. Kemp ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Actin Cytoskeleton ◽  
Energy Homeostasis ◽  
Serum Response Factor ◽  
Regulatory Protein ◽  
Fiber Formation ◽  
Actin Stress Fiber ◽  
Zdf Rat ◽  
Vasp Phosphorylation ◽  
Amp Activated Protein Kinase

Vasodilator-stimulated phosphoprotein (VASP) is an actin regulatory protein that links signaling pathways to remodeling of the cytoskeleton. VASP functions are modulated by protein kinases, which phosphorylate the sites Ser-157, Ser-239, and Thr-278. The kinase responsible for Thr-278 phosphorylation, biological functions of the phosphorylation, and association with disease states have remained enigmatic. Using VASP phosphorylation status-specific antibodies, we identified AMP-activated protein kinase (AMPK), a serine-threonine kinase and fundamental sensor of energy homeostasis, in a screen for kinases that phosphorylate the Thr-278 site of VASP in endothelial cells. Pharmacological AMPK inhibitors and activators and AMPK mutants revealed that the kinase specifically targets residue Thr-278 but not Ser-157 or Ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular F-/G-actin equilibrium, indicated that AMPK-mediated VASP phosphorylation impaired actin stress fiber formation and altered cell morphology. In the Zucker Diabetic Fatty (ZDF) rat model for type II diabetes, AMPK activity and Thr-278 phosphorylation were substantially reduced in arterial vessel walls. These findings suggest that VASP is a new AMPK substrate, that VASP Thr-278 phosphorylation translates metabolic signals into actin cytoskeleton rearrangements, and that this signaling system becomes down-regulated in diabetic vessels.

scholarly journals Dissecting the Role of 5′-AMP for Allosteric Stimulation, Activation, and Deactivation of AMP-activated Protein Kinase

2006 ◽  
Vol 281 (43) ◽  
pp. 32207-32216 ◽  
Author(s):  
Marianne Suter ◽  
Uwe Riek ◽  
Roland Tuerk ◽  
Uwe Schlattner ◽  
Theo Wallimann ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Phosphatase ◽  
Energy Homeostasis ◽  
Adenine Nucleotides ◽  
Enzyme Preparations ◽  
Activity Measurements ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a heterotrimeric protein kinase that is crucial for cellular energy homeostasis of eukaryotic cells and organisms. Here we report on the activation of AMPK α1β1γ1 and α2β2γ1 by their upstream kinases (Ca2+/calmodulin-dependent protein kinase kinase-β and LKB1-MO25α-STRADα), the deactivation by protein phosphatase 2Cα, and on the extent of stimulation of AMPK by its allosteric activator AMP, using purified recombinant enzyme preparations. An accurate high pressure liquid chromatography-based method for AMPK activity measurements was established, which allowed for direct quantitation of the unphosphorylated and phosphorylated artificial peptide substrate, as well as the adenine nucleotides. Our results show a 1000-fold activation of AMPK by the combined effects of upstream kinase and saturating concentrations of AMP. The two AMPK isoforms exhibit similar specific activities (6 μmol/min/mg) and do not differ significantly by their responsiveness to AMP. Due to the inherent instability of ATP and ADP, it proved impossible to assay AMPK activity in the absolute absence of AMP. However, the half-maximal stimulatory effect of AMP is reached below 2 μm. AMP does not appear to augment phosphorylation by upstream kinases in the purified in vitro system, but deactivation by dephosphorylation of AMPK α-subunits at Thr-172 by protein phosphatase 2Cα is attenuated by AMP. Furthermore, it is shown that neither purified NAD+ nor NADH alters the activity of AMPK in a concentration range of 0–300 μm, respectively. Finally, evidence is provided that ZMP, a compound formed in 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside-treated cells to activate AMPK in vivo, allosterically activates purified AMPK in vitro, but compared with AMP, maximal activity is not reached. These data shed new light on physiologically important aspects of AMPK regulation.

scholarly journals Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes

2006 ◽  
Vol 203 (7) ◽  
pp. 1665-1670 ◽  
Author(s):  
Peter Tamás ◽  
Simon A. Hawley ◽  
Rosemary G. Clarke ◽  
Kirsty J. Mustard ◽  
Kevin Green ◽  
...  
Keyword(s):  
Protein Kinase ◽  
T Lymphocytes ◽  
Energy Homeostasis ◽  
Antigen Receptor ◽  
Adenosine Monophosphate ◽  
Ampk Activation ◽  
Serine Kinase ◽  
Cellular Energy ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) has a crucial role in maintaining cellular energy homeostasis. This study shows that human and mouse T lymphocytes express AMPKα1 and that this is rapidly activated in response to triggering of the T cell antigen receptor (TCR). TCR stimulation of AMPK was dependent on the adaptors LAT and SLP76 and could be mimicked by the elevation of intracellular Ca2+ with Ca2+ ionophores or thapsigargin. AMPK activation was also induced by energy stress and depletion of cellular adenosine triphosphate (ATP). However, TCR and Ca2+ stimulation of AMPK required the activity of Ca2+–calmodulin-dependent protein kinase kinases (CaMKKs), whereas AMPK activation induced by increased AMP/ATP ratios did not. These experiments reveal two distinct pathways for the regulation of AMPK in T lymphocytes. The role of AMPK is to promote ATP conservation and production. The rapid activation of AMPK in response to Ca2+ signaling in T lymphocytes thus reveals that TCR triggering is linked to an evolutionally conserved serine kinase that regulates energy metabolism. Moreover, AMPK does not just react to cellular energy depletion but also anticipates it.

scholarly journals Glucose Metabolism and Energy Homeostasis in Mouse Hearts Overexpressing Dominant Negative α2 Subunit of AMP-activated Protein Kinase

2003 ◽  
Vol 278 (31) ◽  
pp. 28372-28377 ◽  
Author(s):  
Yanqiu Xing ◽  
Nicolas Musi ◽  
Nobuharu Fujii ◽  
Liqun Zou ◽  
Ivan Luptak ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Dominant Negative ◽  
Amp Activated Protein Kinase

scholarly journals A Central Role for Neuronal Adenosine 5′-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5220-5229 ◽  
Author(s):  
Eduardo R. Ropelle ◽  
José R. Pauli ◽  
Karina G. Zecchin ◽  
Mirian Ueno ◽  
Cláudio T. de Souza ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Food Intake ◽  
Life Span ◽  
Energy Homeostasis ◽  
Ampk Activation ◽  
Chronic Infusion ◽  
The Central Nervous System ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase ◽  
Cancer Anorexia

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1β, and TNF-α and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.

Sign in / Sign up

Export Citation Format

Share Document