scholarly journals Wnt signalling at the crossroads of nutritional regulation

2008 ◽  
Vol 416 (2) ◽  
pp. e11-e13 ◽  
Author(s):  
Jaswinder K. Sethi ◽  
Antonio J. Vidal-Puig
Keyword(s):  
Protein Kinase ◽  
Glucose Sensing ◽  
Cellular Level ◽  
Wnt Signalling ◽  
Nutritional Regulation ◽  
Biochemical Journal ◽  
Hexosamine Pathway ◽  
Attractive Therapeutic Target ◽  
Sense And Respond ◽  
Living Organisms

The ability to sense and respond to nutritional cues is among the most fundamental processes that support life in living organisms. At the cellular level, a number of biochemical mechanisms have been proposed to mediate cellular glucose sensing. These include ATP-sensitive potassium channels, AMP-activated protein kinase, activation of PKC (protein kinase C), and flux through the hexosamine pathway. Less well known is how cellularly heterogenous organs couple nutrient availability to prioritization of cell autonomous functions and appropriate growth of the entire organ. Yet what is clear is that when such mechanisms fail or become inappropriately active they can lead to dire consequences such as diabetes, metabolic syndromes, cardiovascular diseases and cancer. In this issue of the Biochemical Journal, Anagnostou and Shepherd report the identification of an important link between cellular glucose sensing and the Wnt/β-catenin signalling pathway in macrophages. Their data strongly indicate that the Wnt/β-catenin pathway of Wnt signalling is responsive to physiological concentrations of nutrients but also suggests that that this system could be inappropriately activated in the diabetic (hyperglycaemic) or other metabolically compromised pathological states. This opens the exciting possibility that organ-selective modulation of Wnt signalling may become an attractive therapeutic target to treat these diseases.

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.

Magnitude and variation of ratio of total body potassium to fat-free mass: a cellular level modeling study

2001 ◽  
Vol 281 (1) ◽  
pp. E1-E7 ◽  
Author(s):  
Zimian Wang ◽  
F. Xavier Pi-Sunyer ◽  
Donald P. Kotler ◽  
Jack Wang ◽  
Richard N. Pierson ◽  
...  
Keyword(s):  
Body Fat ◽  
Essential Element ◽  
Physiological Model ◽  
Cellular Level ◽  
Fat Free Mass ◽  
Total Body Potassium ◽  
Fluid Compartment ◽  
Total Body Fat ◽  
Total Body ◽  
Living Organisms

Potassium is an essential element of living organisms that is found almost exclusively in the intracellular fluid compartment. The assumed constant ratio of total body potassium (TBK) to fat-free mass (FFM) is a cornerstone of the TBK method of estimating total body fat. Although the TBK-to-FFM (TBK/FFM) ratio has been assumed constant, a large range of individual and group values is recognized. The purpose of the present study was to undertake a comprehensive analysis of biological factors that cause variation in the TBK/FFM ratio. A theoretical TBK/FFM model was developed on the cellular body composition level. This physiological model includes six factors that combine to produce the observed TBK/FFM ratio. The ratio magnitude and range, as well as the differences in the TBK/FFM ratio between men and women and variation with growth, were examined with the proposed model. The ratio of extracellular water to intracellular water ( E/I) is the major factor leading to between-individual variation in the TBK/FFM ratio. The present study provides a conceptual framework for examining the separate TBK/FFM determinants and suggests important limitations of the TBK/FFM method used in estimating total body fat in humans and other mammals.

AMPK, MAPK and Bax in the heart: some questions answered

2008 ◽  
Vol 412 (2) ◽  
pp. e15-e16 ◽  
Author(s):  
Vilmante Borutaite
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Wide Field ◽  
Biochemical Journal ◽  
Mitogen Activated Protein ◽  
Isolated Cardiac Myocytes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase ◽  
Rapid Activation

The question of how Bax is activated during apoptosis to perform its role in permeabilization of mitochondrial membranes is intriguing for investigators in the wide field of cell death research. In their paper published in the Biochemical Journal in 2006, Capano and Crompton presented their discovery that simulated ischaemia causes rapid activation of AMPK (AMP-activated protein kinase) which phosphorylates and activates p38 MAPK (mitogen-activated protein kinase) leading to Bax activation and translocation to mitochondria in isolated cardiac myocytes. This was the first report on the molecular mechanism of Bax activation and migration during ischaemia-induced apoptosis in cardiomyocytes.

The sweet side of AMPK signaling: regulation of GFAT1

2017 ◽  
Vol 474 (7) ◽  
pp. 1289-1292 ◽  
Author(s):  
John W. Scott ◽  
Jonathan S. Oakhill
Keyword(s):  
Energy Demand ◽  
Dynamic Control ◽  
Cellular Protein ◽  
Post Translational Modification ◽  
Nutrient Metabolism ◽  
Ampk Signaling ◽  
Biochemical Journal ◽  
Signaling Axis ◽  
Hexosamine Biosynthesis ◽  
Living Organisms

Maintaining a steady balance between nutrient supply and energy demand is essential for all living organisms and is achieved through the dynamic control of metabolic processes that produce and consume adenosine-5′-triphosphate (ATP), the universal currency of energy in all cells. A key sensor of cellular energy is the adenosine-5′-monophosphate (AMP)-activated protein kinase (AMPK), which is the core component of a signaling network that regulates energy and nutrient metabolism. AMPK is activated by metabolic stresses that decrease cellular ATP, and functions to restore energy balance by orchestrating a switch in metabolism away from anabolic pathways toward energy-generating catabolic processes. A new study published in a recent issue of Biochemical Journal by Zibrova et al. shows that glutamine:fructose-6-phosphate amidotransferase-1 (GFAT1), the rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), is a physiological substrate of AMPK. The HBP is an offshoot of the glycolytic pathway that drives the synthesis of uridine-5′-diphospho-N-acetylglucosamine, the requisite donor metabolite needed for dynamic β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of cellular proteins. O-GlcNAcylation is a nutrient-sensitive post-translational modification that, like phosphorylation, regulates numerous intracellular processes. Zibrova et al. show that inhibitory phosphorylation of the GFAT1 residue Ser243 by AMPK in response to physiological or small-molecule activators leads to a reduction in cellular protein O-GlcNAcylation. Further work revealed that AMPK-dependent phosphorylation of GFAT1 promotes angiogenesis in endothelial cells. This elegant study demonstrates that the AMPK–GFAT1 signaling axis serves as an important communication point between two nutrient-sensitive signaling pathways and is likely to play a significant role in controlling physiological processes in many other tissues.

Suppression of Synaptotagmin II restrains phorbolester-induced downregulation of protein kinase Cα by diverting the kinase from a degradative pathway to the recycling endocytic compartment

2002 ◽  
Vol 115 (15) ◽  
pp. 3083-3092 ◽  
Author(s):  
Ze Peng ◽  
Elena Grimberg ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
Secretory Granules ◽  
Critical Factor ◽  
Cellular Level ◽  
Endocytic Compartment ◽  
Early Endosomes ◽  
Protein Kinase Cα ◽  
Rbl Cells

Downregulation of protein kinase Cα (PKCα) following long-term exposure to phorbol esters such as TPA is traffic dependent and involves delivery of the active, membrane-associated PKCα to endosomes. In this study, we show that synaptotagmin II (Syt II), a member of the Syt family of proteins, is required for TPA-induced degradation of PKCα. Thus, whereas the kinase half-life in TPA-treated cultured mast cells (the mast cell line rat basophilic leukemia RBL-2H3) is 2 hours, it is doubled in RBL-Syt II- cells, in which the cellular level of Syt II is reduced by>95% by transfection with Syt II antisense cDNA. We demonstrate that in TPA-treated RBL cells, PKCα travels from the cytosol to the plasma membrane, where it is delivered to early endosomes on its route to degradation. By contrast, in TPA-treated RBL-Syt II- cells,PKCα is diverted to recycling endosomes and remains distributed between the plasma membrane and the perinuclear recycling endocytic compartment. Notably, in both RBL and RBL-Syt II- cells, a fraction of PKCα is delivered and maintained in the secretory granules (SG). These results implicate Syt II as a critical factor for the delivery of internalized cargo for degradation. As shown here, one consequence of Syt II suppression is a delay in PKCα downregulation, resulting in its prolonged signaling.

scholarly journals Identification of Cdc37 as a Novel Regulator of the Stress-Responsive Mitogen-Activated Protein Kinase

2003 ◽  
Vol 23 (15) ◽  
pp. 5132-5142 ◽  
Author(s):  
Hisashi Tatebe ◽  
Kazuhiro Shiozaki
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Inflammatory Responses ◽  
Cellular Level ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Survival ◽  
Evolutionarily Conserved ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
The Stability

ABSTRACT Eukaryotic cells utilize multiple mitogen-activated protein kinases (MAPKs) to transmit various extracellular stimuli to the nucleus. A subfamily of MAPKs that mediates environmental stress stimuli is also called stress-activated protein kinase (SAPK), which has crucial roles in cellular survival under stress conditions as well as inflammatory responses. Here we report that Cdc37, an evolutionarily conserved kinase-specific chaperone, is a positive regulator of Spc1 SAPK in the fission yeast Schizosaccharomyces pombe. Through a genetic screen, we have identified cdc37 as a mutation that compromises signaling through Spc1 SAPK. The Cdc37 protein physically interacts with Spc1, and the cdc37 mutation affects both the cellular level of the Spc1 protein and stress-induced Spc1 phosphorylation by Wis1 MAPK kinase (MAPKK). Consistently, expression of the stress response genes regulated by the Spc1 pathway is compromised in cdc37 mutant cells. On the other hand, a mutation in Hsp90, which often cooperates with Cdc37 in chaperoning protein kinases, does not affect Spc1 SAPK. These results suggest that Spc1 SAPK is a novel client protein for the Cdc37 chaperone, and the Cdc37 function is important to maintain the stability of the Spc1 protein and to facilitate stress signaling from Wis1 MAPKK to Spc1 SAPK.

Glucose induces an autocrine activation of the Wnt/β-catenin pathway in macrophage cell lines

2008 ◽  
Vol 416 (2) ◽  
pp. 211-218 ◽  
Author(s):  
Sasha H. Anagnostou ◽  
Peter R. Shepherd
Keyword(s):  
Cell Lines ◽  
Nuclear Translocation ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Macrophage Cell ◽  
Glucose Levels ◽  
Wnt Signalling Pathway ◽  
Hexosamine Pathway ◽  
Number Of Genes ◽  
Canonical Wnt

The canonical Wnt signalling pathway acts by slowing the rate of ubiquitin-mediated β-catenin degradation. This results in the accumulation and subsequent nuclear translocation of β-catenin, which induces the expression of a number of genes involved in growth, differentiation and metabolism. The mechanisms regulating the Wnt signalling pathway in the physiological context is still not fully understood. In the present study we provide evidence that changes in glucose levels within the physiological range can acutely regulate the levels of β-catenin in two macrophage cell lines (J774.2 and RAW264.7 cells). In particular we find that glucose induces these effects by promoting an autocrine activation of Wnt signalling that is mediated by the hexosamine pathway and changes in N-linked glycosylation of proteins. These studies reveal that the Wnt/β-catenin system is a glucose-responsive signalling system and as such is likely to play a role in pathways involved in sensing changes in metabolic status.

Sign in / Sign up

Export Citation Format

Share Document