Inhibiting PTEN

2007 ◽  
Vol 35 (2) ◽  
pp. 257-259 ◽  
Author(s):  
E. Rosivatz
Keyword(s):  
Glucose Uptake ◽  
Drug Target ◽  
Cell Cycle Progression ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Tumour Suppressor ◽  
Key Enzyme ◽  
And Migration ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. In dephosphorylating the 3-position of the inositol ring of phosphoinositides such as PtdIns(3,4,5)P3, PTEN's lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. This is essential for cell motility and migration due to the achievement of a PtdIns(3,4,5)P3/PtdIns(4,5)P2 gradient that is also involved in metastasis. Furthermore, PTEN's tumour suppressor role is linked to the control of cell-cycle progression and cell proliferation by counteracting Akt (also called protein kinase B) signalling which is PtdIns(3,4,5)P3-dependent. Akt is upstream of several kinases involved in proliferation and apoptotic signalling which are often found to be deregulated or mutated in tumours. However, Akt is also the key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore PTEN has recently moved into the spotlight as a drug target in diabetes. This review summarizes studies undertaken on PTEN's role in glucose uptake, insulin resistance, diabetes and its controversial role in GLUT (glucose transporter)-mediated glucose uptake. Currently available techniques for inhibiting PTEN and the suitability of PTEN as a drug target will be discussed.

Substrate specificity and acute regulation of the tumour suppressor phosphatase, PTEN

2007 ◽  
Vol 74 ◽  
pp. 69-80 ◽  
Author(s):  
C. Peter Downes ◽  
Nevin Perera ◽  
Sarah Ross ◽  
Nick R. Leslie
Keyword(s):  
Protein Phosphatase ◽  
Current Model ◽  
Tumour Suppressor ◽  
Protein Substrates ◽  
Dual Specificity ◽  
Survival And Growth ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue ◽  
A Current ◽  
Inhibit Cell Proliferation

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumour suppressor that functions as a PtdIns(3,4,5)P3 3-phosphatase to inhibit cell proliferation, survival and growth by antagonizing PI3K (phosphoinositide 3-kinase)-dependent signalling. Recent work has begun to focus attention on potential biological functions of the protein phosphatase activity of PTEN and on the possibility that some of its functions are phosphatase-independent. We discuss here the structural and regulatory mechanisms that account for the remarkable specificity of PTEN with respect to its PtdIns substrates and how it avoids the soluble headgroups of PtdIns that occur commonly in cells. Secondly we discuss the concept of PTEN as a constitutively active enzyme that is subject to negative regulation both physiologically and pathologically. Thirdly, we review the evidence that PTEN functions as a dual specificity phosphatase with discrete lipid and protein substrates. Lastly we present a current model of how PTEN may participate in the control of cell migration.

The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4

2008 ◽  
Vol 412 (2) ◽  
pp. 331-338 ◽  
Author(s):  
Younghee Ahn ◽  
Chae Young Hwang ◽  
Seung-Rock Lee ◽  
Ki-Sun Kwon ◽  
Cheolju Lee
Keyword(s):  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Tumour Suppressor ◽  
Pcr Analysis ◽  
Multifunctional Protein ◽  
Ubiquitin Protein Ligase ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue ◽  
Nih 3T3 ◽  
Gene 4

The tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10; a phosphatidylinositol 3-phosphatase) is a multifunctional protein deregulated in many types of cancer. It is suggested that a number of proteins that relate with PTEN functionally or physically have not yet been found. In order to search for PTEN-interacting proteins that might be crucial in the regulation of PTEN, we exploited a proteomics-based approach. PTEN-expressing NIH 3T3 cell lysates were used in affinity chromatography and then analysed by LC–ESI–MS/MS (liquid chromatography–electrospray ionization–tandem MS). A total of 93 proteins were identified. Among the proteins identified, we concentrated on the E3 ubiquitin-protein ligase Nedd4 (neural-precursor-cell-expressed, developmentally down-regulated gene 4), and performed subsequent validation experiments using HeLa cells. Nedd4 inhibited PTEN-induced apoptotic cell death and, conversely, the Nedd4 level was down-regulated by PTEN. The down-regulation effect was diminished by a mutation (C124S) in the catalytic site of PTEN. Nedd4 expression was also decreased by a PI3K (phosphoinositide 3-kinase) inhibitor, LY294002, suggesting that the regulation is dependent on the phosphatase-kinase activity of the PTEN-PI3K/Akt pathway. Semi-quantitative real-time PCR analysis revealed that Nedd4 was transcriptionally regulated by PTEN. Thus our results have important implications regarding the roles of PTEN upon the E3 ubquitin ligase Nedd4 as a negative feedback regulator as well as a substrate.

scholarly journals A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes

2019 ◽  
Vol 20 (21) ◽  
pp. 5443 ◽  
Author(s):  
Takenaka ◽  
Nakao ◽  
Matsui ◽  
Satoh
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Specific Inhibitor ◽  
Small Gtpase ◽  
Glut4 Translocation ◽  
Insulin Dependent ◽  
Mouse Adipocytes ◽  
Phosphoinositide 3 Kinase

Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, the small GTPase Rac1 plays an important role downstream of Akt2 in the regulation of insulin-stimulated glucose uptake. However, the role for Rac1 in adipocytes remains controversial. Here, we show that Rac1 is required for insulin-dependent GLUT4 translocation also in adipocytes. A Rac1-specific inhibitor almost completely suppressed GLUT4 translocation induced by insulin or a constitutively activated mutant of phosphoinositide 3-kinase or Akt2. Constitutively activated Rac1 also enhanced GLUT4 translocation. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was abrogated by inhibition of phosphoinositide 3-kinase or Akt2. On the other hand, constitutively activated Akt2 caused Rac1 activation, and insulin-induced Rac1 activation was suppressed by an Akt2-specific inhibitor. Moreover, GLUT4 translocation induced by a constitutively activated mutant of Akt2 or Rac1 was diminished by knockdown of another small GTPase RalA. RalA was activated by a constitutively activated mutant of Akt2 or Rac1, and insulin-induced RalA activation was suppressed by an Akt2- or Rac1-specific inhibitor. Collectively, these results suggest that Rac1 plays an important role in the regulation of insulin-dependent GLUT4 translocation downstream of Akt2, leading to RalA activation in adipocytes.

scholarly journals Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes

2005 ◽  
Vol 386 (3) ◽  
pp. 471-478 ◽  
Author(s):  
Pablo STROBEL ◽  
Claudio ALLARD ◽  
Tomás PEREZ-ACLE ◽  
Rosario CALDERON ◽  
Rebeca ALDUNATE ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Glucose Uptake ◽  
Protein Tyrosine Kinase ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Biological Activities ◽  
Inhibition Mechanism ◽  
Protein Data Bank Code ◽  
Protein Tyrosine ◽  
Comparative Model

The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10–100 μM. These three flavonoids show a competitive pattern of inhibition, with Ki=16, 33.5 and 90 μM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.

scholarly journals Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Fang Huang ◽  
Jie Chen ◽  
Jingwen Wang ◽  
Pingping Zhu ◽  
Wenting Lin
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Glucose Transporter ◽  
High Fatty Acid ◽  
Luciferase Reporter ◽  
High Concentrations ◽  
Novel Target ◽  
Phosphoinositide 3 Kinase

Obesity-related insulin resistance and high fatty acid concentrations occur during the development of type 2 diabetes mellitus. The role of high concentrations of plasma-free fatty acids is not fully understood. In this study, palmitic acid (PA, 0.8 mM for 24 h) induced the expression of miR-221 that bound to phosphoinositide 3-kinases (PI3K) mRNA to inhibit glucose uptake by HepG2 cells. Compared with controls, PA significantly decreased glucose uptake, increased insulin receptor substrate-2 (IRS-2) and miR-221 expression, and decreased phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter type 4 (GLUT4) mRNA expression. Luciferase reporter assay revealed that miR-221 binding inhibited PI3K expression. Transfection of HepG2 cells with an miR-221 mimic induced miR-221 expression and inhibited the PI3K/AKT pathway. PA decreased glucose uptake in HepG2 cells by inducing the expression of miR-221, which bound to PI3K mRNA and suppressed PI3K/AKT signaling. miR-221 may be a novel target for preventing and treating obesity-induced insulin resistance.

scholarly journals Atrophy of White Adipose Tissue Accompanied with Decreased Insulin-Stimulated Glucose Uptake in Mice Lacking the Small GTPase Rac1 Specifically in Adipocytes

2021 ◽  
Vol 22 (19) ◽  
pp. 10753
Author(s):  
Kiko Hasegawa ◽  
Nobuyuki Takenaka ◽  
Kenya Tanida ◽  
Man Piu Chan ◽  
Mizuki Sakata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Physiological Role ◽  
Small Gtpase ◽  
Mrna Levels ◽  
Glut4 Translocation ◽  
White Adipocytes ◽  
Phosphoinositide 3 Kinase

Insulin stimulates glucose uptake in adipose tissue and skeletal muscle by inducing plasma membrane translocation of the glucose transporter GLUT4. Although the small GTPase Rac1 is a key regulator downstream of phosphoinositide 3-kinase (PI3K) and the protein kinase Akt2 in skeletal muscle, it remains unclear whether Rac1 also regulates glucose uptake in white adipocytes. Herein, we investigated the physiological role of Rac1 in white adipocytes by employing adipocyte-specific rac1 knockout (adipo-rac1-KO) mice. Subcutaneous and epididymal white adipose tissues (WATs) in adipo-rac1-KO mice showed significant reductions in size and weight. Actually, white adipocytes lacking Rac1 were smaller than controls. Insulin-stimulated glucose uptake and GLUT4 translocation were abrogated in rac1-KO white adipocytes. On the other hand, GLUT4 translocation was augmented by constitutively activated PI3K or Akt2 in control, but not in rac1-KO, white adipocytes. Similarly, to skeletal muscle, the involvement of another small GTPase RalA downstream of Rac1 was demonstrated. In addition, mRNA levels of various lipogenic enzymes were down-regulated in rac1-KO white adipocytes. Collectively, these results suggest that Rac1 is implicated in insulin-dependent glucose uptake and lipogenesis in white adipocytes, and reduced insulin responsiveness due to the deficiency of Rac1 may be a likely explanation for atrophy of WATs.

The tuberous sclerosis complex (TSC) pathway and mechanism of size control

2003 ◽  
Vol 31 (3) ◽  
pp. 584-586 ◽  
Author(s):  
C.J. Potter ◽  
L.G. Pedraza ◽  
H. Huang ◽  
T. Xu
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Insulin Signalling ◽  
Size Control ◽  
Genetic Screens ◽  
Tissue Size ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue ◽  
Deficient Mice ◽  
Growth Constraint

We have identified three groups of growth-constraint genes using mosaic genetic screens in Drosophila melanogaster, including PTEN (phosphatase and tensin homologue deleted on chromosome 10), and the tuberous sclerosis complex (TSC) genes, Tsc1 and Tsc2. Our studies show that all three groups of genes participate in mechanisms that regulate organ and organism size in animals. We propose that mechanisms of organ size control are critical targets for diseases, such as tumorigenesis, which require an increase in tissue size and total mass, and for evolutionary events that alter the size of organisms. Using genetic and biochemical methods, we have shown that Tsc1 and Tsc2 function in the insulin/phosphoinositide 3-kinase (PI3K)/Akt pathway. We have shown that Akt regulates the Tsc1–Tsc2 complex by directly phosphorylating Tsc2. We have shown further that S6 kinase (S6K) is a downstream component of the PI3K/Akt/TSC pathway and reduction of S6K activity can block TSC defects. Recent studies from many laboratories have now confirmed our findings in mice, rats and human patients, and have shown that drugs that antagonize S6K activities, such as rapamycin, diminish tumours in TSC-deficient mice and rats. Clinical trials based on these findings have begun. Given that other components of the pathway, such as PTEN, are also mutated in a large number of cancer patients and that these components regulate intracellular insulin signalling, therapeutics based on the knowledge of the pathway could have effects beyond the TSC patient population.

scholarly journals Characterising hyperinsulinemia-induced insulin resistance in human skeletal muscle cells

2020 ◽  
Vol 64 (3) ◽  
pp. 125-132 ◽  
Author(s):  
Mark C Turner ◽  
Neil R W Martin ◽  
Darren J Player ◽  
Richard A Ferguson ◽  
Patrick Wheeler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Human Skeletal Muscle ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Insulin Stimulation ◽  
Healthy Human ◽  
Glucose Transporter 1 ◽  
Human Skeletal Muscle Cells

Hyperinsulinaemia potentially contributes to insulin resistance in metabolic tissues, such as skeletal muscle. The purpose of these experiments was to characterise glucose uptake, insulin signalling and relevant gene expression in primary human skeletal muscle-derived cells (HMDCs), in response to prolonged insulin exposure (PIE) as a model of hyperinsulinaemia-induced insulin resistance. Differentiated HMDCs from healthy human donors were cultured with or without insulin (100 nM) for 3 days followed by an acute insulin stimulation. HMDCs exposed to PIE were characterised by impaired insulin-stimulated glucose uptake, blunted IRS-1 phosphorylation (Tyr612) and Akt (Ser473) phosphorylation in response to an acute insulin stimulation. Glucose transporter 1 (GLUT1), but not GLUT4, mRNA and protein increased following PIE. The mRNA expression of metabolic (PDK4) and inflammatory markers (TNF-α) was reduced by PIE but did not change lipid (SREBP1 and CD36) or mitochondrial (UCP3) markers. These experiments provide further characterisation of the effects of PIE as a model of hyperinsulinaemia-induced insulin resistance in HMDCs.

scholarly journals Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells under Hypoxic and Low-Glucose Conditions

2020 ◽  
Author(s):  
Shui-Hong Zhou ◽  
Xiao-Hong Chen ◽  
Jia Liu ◽  
Jiang-Tao Zhong ◽  
Jun Fan
Keyword(s):  
Stem Cells ◽  
Glucose Uptake ◽  
Laryngeal Carcinoma ◽  
Glucose Transporter ◽  
Cell Counting ◽  
Glucose Transporter 1 ◽  
Glut 1 ◽  
Low Glucose ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Enhanced glucose uptake and autophagy are means by which cells adapt to stressful microenvironments. We investigated the roles of glucose transporter-1 (GLUT-1) and autophagy in laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.Methods: CD133+ Tu212 laryngeal carcinoma stem cells were purified by magnetic-activated cell sorting and subjected to hypoxic and/or low-glucose conditions. Proliferation was evaluated using a cell-counting kit and a clone-formation assay, and migration was evaluated through a Transwell assay. Autophagy was assessed via transmission electron microscopy. GLUT-1 and beclin-1 expression were silenced using an shRNA and autophagy was manipulated using rapamycin, 3-MA, or chloroquine. Gene expression levels were evaluated by quantitative reverse transcription-polymerase chain reaction and protein concentrations were assessing via Western blotting.Results: Compared to CD133– stem cells, CD133+ cells showed increased proliferation and migration, and reduced apoptosis, under hypoxic or low-glucose conditions. They also showed increased expression of GLUT-1 and autophagy markers. Finally, GLUT-1 knockdown or autophagy inhibition reduced their proliferation and migration.Conclusions: Enhanced glucose uptake and autophagy maintain the functions of CD133+ laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.

The regulation of cell migration by PTEN

2005 ◽  
Vol 33 (6) ◽  
pp. 1507-1508 ◽  
Author(s):  
N.R. Leslie ◽  
X. Yang ◽  
C.P. Downes ◽  
C.J. Weijer
Keyword(s):  
Cell Migration ◽  
Phosphatase Activity ◽  
Tumour Suppressor ◽  
Chromosome 10 ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Directed Cell Migration ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

In vertebrates, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) regulates many cellular processes through its PtdIns(3,4,5)P3 lipid phosphatase activity, antagonizing PI3K (phosphoinositide 3-kinase) signalling. Given the important role of PI3Ks in the regulation of directed cell migration and the role of PTEN as an inhibitor of migration, it is somewhat surprising that data now indicate that PTEN is able to regulate cell migration independent of its lipid phosphatase activity. Here, we discuss the role of PTEN in the regulation of cell migration.

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