Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute exercise performance represents a major metabolic challenge for the skeletal muscle, but also for the liver as the most important source of energy. However the molecular adaptation of the liver to one single bout of exercise is largely unknown. C57BL/6 mice performed a 60 min treadmill run at high aerobic intensity. Liver, soleus and white gastrocnemius muscle were removed immediately after exercise. The single bout of exercise resulted in a very rapid and pronounced induction of hepatic metabolic enzymes and regulators of metabolism or transcription: glucose-6-phosphatase (G6Pase; 3-fold), pyruvate dehydrogenase kinase-4 (PDK4; 4.8-fold), angiopoietin-like 4 (2.1-fold), insulin receptor substrate (IRS)-2 (5.1-fold), peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha; 3-fold). In soleus and white gastrocnemius muscle the up-regulation of IRS-2 and PDK4 was less pronounced compared with the liver and no significant induction of PGC-1alpha could be detected at this early time point. Activation of AMPK was found in both liver and white gastrocnemius muscle as phosphorylation of Thr-172. The induction of endogenous insulin secretion by a glucose load directly after the exercise bout resulted in a significantly higher PKB/Akt phosphorylation in the liver of exercised mice. The markedly enhanced IRS-2 protein amount, and presumably reduced serine/threonine phosphorylation of the IRS proteins induced by the acute exercise could be responsible for this enhanced action of insulin. In conclusion, acute exercise induced a rapid and pronounced transcriptional adaptation in the liver, and regulated hepatic IRS proteins leading to improved cellular insulin signal transduction.
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PMID:Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise. 1900 Oct 47

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21-24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-kappaB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p<0.05), p66Shc/phospho-p66 (p<0.05), Bax/Bcl-2 ratio (p<0.05) and NF-kappaB expression (p<0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p<0.001) and WKYs (p<0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD.
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PMID:Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease. 1904 34

Exercise results in an increase in interleukin-6 (IL-6), its receptor (IL-6R) and skeletal muscle glucose transport. Interleukin-6 has been found to have equivocal effects on glucose transport, with no studies, to our knowledge, investigating any potential role of IL-6R. In the present study, we hypothesized that a combined preparation of IL-6 and soluble IL-6R (sIL-6R) would stimulate glucose transport. Mouse soleus muscles were incubated with physiological and supraphysiological concentrations of IL-6 and a combination of IL-6 and sIL-6R. Total and phosphorylated AMP-activated protein kinase (AMPK) and Protein Kinase B (PKB/Akt) were also measured by Western blotting. Exposure to both physiological (80 pg ml(-1)) and supraphysiological IL-6 (120 ng ml(-1)) had no effect on glucose transport. At physiological levels, exposure to a combination of IL-6 and sIL-6R (32 ng ml(-1)) resulted in a 1.4-fold increase (P < 0.05) in basal glucose transport with no change to the phosphorylation of AMPK. Exposure to supraphysiological levels of IL-6 and sIL-6R (120 ng ml(-1)) resulted in an approximately twofold increase (P < 0.05) in basal glucose transport and an increase (P < 0.05) in AMPK phosphorylation. No effect of IL-6 or sIL-6R was observed on insulin-stimulated glucose transport. These findings demonstrate that, while IL-6 alone does not stimulate glucose transport in mouse soleus muscle, when sIL-6R is introduced glucose transport is directly stimulated, partly through AMPK-dependent signalling.
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PMID:The effect of interleukin-6 and the interleukin-6 receptor on glucose transport in mouse skeletal muscle. 1948 99

By interfering with signal transduction events that control cell proliferation and fate, kinase inhibitors (KIs) hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in off-target cells could lead to side effects. For instance, this context dependence renders many KIs potentially cardiotoxic since inhibition of primary cancer targets such as ABL, RAF1 or AMPK recruits pro-apoptotic pathways in cardiomyocytes. Motivated by these observations, we propose a mode of 'therapeutic editing' where one drug (the editor) suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, and the editor suppresses the downstream propagation of toxicity-related signaling.
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PMID:Selective antagonism of anticancer drugs for side-effect removal. 1959 65

Sertoli cells provide the physical support and the necessary environment for germ cell development. Among the products secreted by Sertoli cells, lactate, the preferred energy substrate for spermatocytes and spermatids, is present. Considering the essential role of lactate on germ cell metabolism, it is supposed that Sertoli cells must ensure its production even in adverse conditions, such as those that would result from a decrease in glucose levels in the extracellular milieu. The aim of the present study was to investigate 1) a possible effect of glucose deprivation on glucose uptake and on the expression of glucose transporters in rat Sertoli cells and 2) the participation of different signal transduction pathways in the above-mentioned regulation. Results obtained show that decreasing glucose levels in Sertoli cell culture medium provokes 1) an increase in glucose uptake accompanied by only a slight decrease in lactate production, 2) an increase in GLUT1 and a decrease in GLUT3 expression, and 3) an activation of AMP-activated protein kinase (AMPK)-, phosphatidylinositol 3-kinase (PI3K)/PKB-, and p38 MAPK-dependent pathways. Additionally, by using specific inhibitors of these pathways, a possible participation of AMPK- and p38MAPK-dependent pathways in the regulation of glucose uptake and GLUT1 expression is shown. These results suggest that Sertoli cells adapt to conditions of glucose deprivation to ensure an adequate lactate concentration in the microenvironment where germ cell development occurs.
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PMID:Molecular mechanisms involved in Sertoli cell adaptation to glucose deprivation. 1963 10

Central leptin action requires PI3K activity to modulate glucose homeostasis and peripheral metabolism. However, the mechanism behind this phenomenon is not clearly understood. We hypothesize that hypothalamic PI3K activity is important for the modulation of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway, PGC1 alpha, and AKT in skeletal muscle (SM). To address this issue, we injected leptin into the lateral ventricle of rats. Hypothalamic JAK2 and AKT were activated by intracerebroventricular (ICV) injection of leptin in a time-dependent manner. Central leptin improved tolerance to glucose (GTT), increased PGC1 alpha expression, and AKT, AMPK, ACC and JAK2 phosphorylation in the soleus muscle. Previous ICV administration of either LY294002 or propranolol (IP) blocked these effects. We concluded that the activation of the hypothalamic PI3K pathway is important for leptin-induced AKT phosphorylation, as well as for active catabolic pathway through AMPK and PGC1 alpha in SM. Thus, a defective leptin signalling PI3K pathway in the hypothalamus may contribute to peripheral resistance to insulin associated to diet-induced obesity.
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PMID:Central leptin action improves skeletal muscle AKT, AMPK, and PGC1 alpha activation by hypothalamic PI3K-dependent mechanism. 1969 60

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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PMID:Recent advances in understanding leptin signaling and leptin resistance. 1972 19

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
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PMID:Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. 1992 52

p27Kip1 (p27) tumour suppressor protein is regulated by multiple mechanisms including its turnover, localization and complex formation with its key targets, cyclin-dependent kinases (CDK) and cyclins. We have earlier shown that p27 exists in cells in a form that lacks cyclin/CDK interactions (hence non-CDK, p27(NCDK)) but the nature of p27(NCDK) has remained unresolved. Here we demonstrate that the epitope recognized by the p27(NCDK)-specific antibody resides in the p27 CDK-interaction domain and that p27(NCDK) is regulated by the balance of CDK inhibitors and cyclin-CDK complexes. We find that signalling by cellular growth promoting pathways, like phosphoinositol 3-kinase (PI3K) and specifically Akt/PKB kinase, inversely correlates with p27(NCDK) levels whereas total p27 levels are unaffected. p27(NCDK), but not total p27, is increased by cellular perturbations such as hyperosmotic and metabolic stress and activation of AMP-activated protein kinase (AMPK). By using AMPK catalytic subunit proficient and deficient cells we further demonstrate that the AMPK pathway governs p27(NCDK) responses to metabolic stress and PI3K inhibition. These results indicate that p27(NCDK) is a sensitive marker for both cell stress and proliferation over and above p27 and is regulated by Akt/PKB and AMPK pathways.
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PMID:Non-CDK-bound p27 (p27(NCDK)) is a marker for cell stress and is regulated through the Akt/PKB and AMPK-kinase pathways. 2003 35

Berberine has been shown to have insulin-sensitizing effect, but the molecular mechanism underlying remains elusive. In this work, we investigated the effect of berberine on insulin-induced signal transduction and glucose uptake in both insulin-sensitive and insulin-resistant rat skeletal muscle cells. Berberine increased the activity of AMPK and PKCzeta and AS160 phosphorylation in normal cells, but had little effect on PKB activation. In insulin-resistant state, berberine exhibited synergistic effect on insulin-induced glucose uptake and GLUT4 translocation. Berberine improved insulin-induced tyrosine-phosphorylation of IRS-1 and the recruitment of p85 to IRS-1. These changes were accompanied by enhancement in insulin-induced PKCzeta and PKB activity and actin remodeling. The ameliorated insulin signal transduction was related to the inhibition of mTOR by berberine, which attenuated serine-phosphorylation of IRS-1. These results suggest that berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells.
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PMID:Berberine modulates insulin signaling transduction in insulin-resistant cells. 2003 10


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