scholarly journals Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase

2011 ◽  
Vol 439 (2) ◽  
pp. 265-275 ◽  
Author(s):  
Carlos Romá-Mateo ◽  
Maria del Carmen Solaz-Fuster ◽  
José Vicente Gimeno-Alcañiz ◽  
Vikas V. Dukhande ◽  
Jordi Donderis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Disorder ◽  
Critical Role ◽  
Glycogen Metabolism ◽  
Lafora Disease ◽  
Gene Encoding ◽  
Dual Specificity Phosphatase ◽  
Progressive Myoclonus Epilepsy ◽  
Dual Specificity ◽  
Amp Activated Protein Kinase

Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser25 as the residue involved in this modification. We also show that Ser25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. The results of the present study suggest that phosphorylation of laforin-Ser25 by AMPK provides a mechanism to modulate the interaction between laforin and malin. Regulation of this complex is necessary to maintain normal glycogen metabolism. Importantly, Ser25 is mutated in some LD patients (S25P), and our results begin to elucidate the mechanism of disease in these patients.

scholarly journals The Laforin–Malin Complex, Involved in Lafora Disease, Promotes the Incorporation of K63-linked Ubiquitin Chains into AMP-activated Protein Kinase β Subunits

2010 ◽  
Vol 21 (15) ◽  
pp. 2578-2588 ◽  
Author(s):  
Daniel Moreno ◽  
Mhairi C. Towler ◽  
D. Grahame Hardie ◽  
Erwin Knecht ◽  
Pascual Sanz
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Disorder ◽  
Energy Status ◽  
Lafora Disease ◽  
Progressive Myoclonus Epilepsy ◽  
Dual Specificity ◽  
Steady State Levels ◽  
Dual Specificity Protein Phosphatase ◽  
Specificity Protein ◽  
Amp Activated Protein Kinase

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 (α, β, and γ) are expressed individually in the cell, and it also occurs on AMPKβ 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 AMPKβ 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 AMPKβ subunits.

The mechanism of protein kinase regulation by protein phosphatases

2001 ◽  
Vol 29 (4) ◽  
pp. 385-391 ◽  
Author(s):  
D. Barford
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Protein Kinases ◽  
Protein Phosphatases ◽  
Important Class ◽  
Cyclin Dependent Kinase ◽  
Receptor Kinase ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Insulin Receptor Kinase

Protein kinases are an important class of substrate of the protein phosphatases. We have examined the mechanism of dephosphorylation of the activation segments of the insulin receptor kinase and cyclin-dependent kinase 2 by their respective phosphatases, namely the tyrosine specific phosphatase PTP1B and the dual specificity phosphatase KAP. These studies reveal that PTP1B and KAP utilize contrasting mechanisms in order to dephosphorylate their substrates specifically.

scholarly journals MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

2018 ◽  
Vol 11 (549) ◽  
pp. eaar3721 ◽  
Author(s):  
Bishuang Cai ◽  
Canan Kasikara ◽  
Amanda C. Doran ◽  
Rajasekhar Ramakrishnan ◽  
Raymond B. Birge ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Calmodulin Dependent ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Inflammation Resolution

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca2+ concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX–derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

Regulation of mammalian acetyl-CoA carboxylase

2002 ◽  
Vol 30 (6) ◽  
pp. 1059-1064 ◽  
Author(s):  
M. R. Munday
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Critical Role ◽  
Physiological Role ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase

Acetyl-CoA carboxylase (ACC) plays a critical role in the regulation of fatty acid metabolism and its two isoforms, ACCα and ACCβ, appear to have distinct functions in the control of fatty acid synthesis and fatty acid oxidation, respectively. They are regulated by similar short-term mechanisms of allosteric activation by citrate, and reversible phosphorylation and inactivation, and there is clearly interaction between these mechanisms. AMP-activated protein kinase is the important physiological ACC kinase for both isoforms and yet there is a potential physiological role for cAMP-dependent protein kinase in the hormonally mediated inactivation of ACCα, and phosphorylation of ACCβ in its unique N-terminus.

scholarly journals Novel Tyrosine Kinase-Mediated Phosphorylation With Dual Specificity Plays a Key Role in the Modulation of Streptococcus pyogenes Physiology and Virulence

2021 ◽  
Vol 12 ◽  
Author(s):  
Sashi Kant ◽  
Vijay Pancholi
Keyword(s):  
Tyrosine Kinase ◽  
Streptococcus Pyogenes ◽  
Catalytic Domain ◽  
Critical Role ◽  
Fine Tuning ◽  
Gene Encoding ◽  
Orphan Gene ◽  
Dual Specificity ◽  
A Genome ◽  
A549 Lung

Streptococcus pyogenes (Group A Streptococcus, GAS) genomes do not contain a gene encoding a typical bacterial-type tyrosine kinase (BY-kinase) but contain an orphan gene-encoding protein Tyr-phosphatase (SP-PTP). Hence, the importance of Tyr-phosphorylation is underappreciated and not recognized for its role in GAS pathophysiology and pathogenesis. The fact that SP-PTP dephosphorylates Abl-tyrosine kinase-phosphorylated myelin basic protein (MBP), and SP-STK (S. pyogenes Ser/Thr kinase) also autophosphorylates its Tyr101-residue prompted us to identify a putative tyrosine kinase and Tyr-phosphorylation in GAS. Upon a genome-wide search of kinases possessing a classical Walker motif, we identified a non-canonical tyrosine kinase M5005_Spy_1476, a ∼17 kDa protein (153 aa) (SP-TyK). The purified recombinant SP-TyK autophosphorylated in the presence of ATP. In vitro and in vivo phosphoproteomic analyses revealed two key phosphorylated tyrosine residues located within the catalytic domain of SP-TyK. An isogenic mutant lacking SP-TyK derived from the M1T1 strain showed a retarded growth pattern. It displayed defective cell division and long chains with multiple parallel septa, often resulting in aggregates. Transcriptomic analysis of the mutant revealed 287 differentially expressed genes responsible for GAS pathophysiology and pathogenesis. SP-TyK also phosphorylated GAS CovR, WalR, SP-STP, and SDH/GAPDH proteins with dual specificity targeting their Tyr/Ser/Thr residues as revealed by biochemical and mass-spectrometric-based phosphoproteomic analyses. SP-TyK-phosphorylated CovR bound to PcovR efficiently. The mutant displayed sustained release of IL-6 compared to TNF-α during co-culturing with A549 lung cell lines, attenuation in mice sepsis model, and significantly reduced ability to adhere to and invade A549 lung cells and form biofilms on abiotic surfaces. SP-TyK, thus, plays a critical role in fine-tuning the regulation of key cellular functions essential for GAS pathophysiology and pathogenesis through post-translational modifications and hence, may serve as a promising target for future therapeutic developments.

scholarly journals Critical role of AMP-activated protein kinase in the balance between mitophagy and mitochondrial biogenesis in MELAS disease

2015 ◽  
Vol 1852 (11) ◽  
pp. 2535-2553 ◽  
Author(s):  
Juan Garrido-Maraver ◽  
Marina Villanueva Paz ◽  
Mario D. Cordero ◽  
Juan Bautista-Lorite ◽  
Manuel Oropesa-Ávila ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Biogenesis ◽  
Critical Role ◽  
Amp Activated Protein Kinase

scholarly journals Role of Hypothalamic Adenosine 5′-Monophosphate-Activated Protein Kinase in the Impaired Counterregulatory Response Induced by Repetitive Neuroglucopenia

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1367-1375 ◽  
Author(s):  
Thierry Alquier ◽  
Junji Kawashima ◽  
Youki Tsuji ◽  
Barbara B. Kahn
Keyword(s):  
Protein Kinase ◽  
Glycogen Content ◽  
Glucose Sensor ◽  
Critical Role ◽  
Glucose Sensing ◽  
Dorsomedial Hypothalamus ◽  
Hormone Responses ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Antecedent hypoglycemia blunts counterregulatory responses that normally restore glycemia, a phenomenon known as hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to impaired counterregulatory responses are largely unknown. Hypothalamic AMP-activated protein kinase (AMPK) acts as a glucose sensor. To determine whether failure to activate AMPK could be involved in the etiology of HAAF, we developed a model of HAAF using repetitive intracerebroventricular (icv) injection of 2-deoxy-d-glucose (2DG) resulting in transient neuroglucopenia in normal rats. Ten minutes after a single icv injection of 2DG, both α1- and α2-AMPK activities were increased 30–50% in arcuate and ventromedial/dorsomedial hypothalamus but not in other hypothalamic regions, hindbrain, or cortex. Increased AMPK activity persisted in arcuate hypothalamus at 60 min after 2DG injection when serum glucagon and corticosterone levels were increased 2.5- to 3.4-fold. When 2DG was injected icv daily for 4 d, hypothalamic α1- and α2-AMPK responses were markedly blunted in arcuate hypothalamus, and α1-AMPK was also blunted in mediobasal hypothalamus 10 min after 2DG on d 4. Both AMPK isoforms were activated normally in arcuate hypothalamus at 60 min. Counterregulatory hormone responses were impaired by recurrent neuroglucopenia and were partially restored by icv injection of 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, an AMPK activator, before 2DG. Glycogen content increased 2-fold in hypothalamus after recurrent neuroglucopenia, suggesting that glycogen supercompensation could be involved in down-regulating the AMPK glucose-sensing pathway in HAAF. Thus, activation of hypothalamic AMPK may be important for the full counterregulatory hormone response to neuroglucopenia. Furthermore, impaired or delayed AMPK activation in specific hypothalamic regions may play a critical role in the etiology of HAAF.

AMP-activated protein kinase regulation and action in skeletal muscle during exercise

2003 ◽  
Vol 31 (1) ◽  
pp. 191-195 ◽  
Author(s):  
N. Musi ◽  
H. Yu ◽  
L.J. Goodyear
Keyword(s):  
Protein Kinase ◽  
Exercise Training ◽  
Metabolic Pathways ◽  
Acute Exercise ◽  
Glycogen Content ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Ampk Activity ◽  
Energy Sensing ◽  
Amp Activated Protein Kinase

Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is strongly activated during muscle contraction due to acute decreases in ATP/AMP and phosphocreatine/creatine ratios. Accumulating evidence suggests that AMPK plays an important role in mediating these metabolic processes. Furthermore, AMPK has been implicated in regulating gene transcription and therefore may play a role in some of the cellular adaptations to training exercise. There is also evidence that changes in AMPK activity result in altered cellular glycogen content, suggesting that this enzyme regulates glycogen metabolism. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. In summary, AMPK regulates several metabolic pathways during acute exercise and modifies the expression of many genes involved in the adaptive changes to exercise training.

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