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

---

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

To evaluate the oxidative stress-related parameters and to determine their order of appearance in the brain aging process, radionuclide experiments were carried out on male DBF1 mice at 3, 12, 24 and 30 months of age. The content of nonprotein sulfhydryl compounds, mainly glutathione, was estimated with technetium-99m meso-hexamethyl propyleneamine oxime ([99mTc]meso-HMPAO) tissue sampling. Glucose transport and metabolism was examined with [1-14C]2-deoxy-D-glucose (2-DG) tissue sampling. Mitochondrial electron transport function was estimated with [15O]O2 gas-tissue ARG. [99mTc]Meso-HMPAO uptake in brain expressed as standardized uptake value (SUV), (radioactivity in brain tissue/tissue weight)/(total administered radioactivity/body weight), reached maximum at 12 months of age and decreased at 24 and 30 months of age in every region examined. The pattern of 2-DG, expressed as SUV, showed a tendency to increase rather than decrease with aging. [15O]O2 fixation in brain slices remained constant until 24 months, while it decreased significantly at 30 months of age. The results suggested the possibility of using imaging techniques in vivo for longitudinal evaluation of the aging process and indicated reduction of nonprotein sulfhydryl compounds including GSH at the early stages of aging may also accelerate the dysfunction of mitochondrial electron transport and neurodegeneration.
...
PMID:Age-related changes of glutathione content, glucose transport and metabolism, and mitochondrial electron transfer function in mouse brain. 1118 61

Protein kinase B/Akt (PKB/Akt) is activated by phosphatidylinositol 3-kinase (PI 3-K) and is a central mediator of cellular proliferation and protection against apoptosis. Insulin, insulin-like growth factor (IGF-1), and glucagon-like peptide-1 (GLP-1) act as glucose-dependent growth factors for pancreatic beta-cells. We assessed signaling pathways and stimulation patterns of PKB/Akt activation by these ligands in the beta-cell line INS-1. Insulin, IGF-1, and GLP-1 induced distinctive time dependent, dose dependent, and glucose dependent phosphorylation of PKB/Akt. Insulin and IGF-1 stimulated PI 3-K activity was mainly associated with insulin receptor substrate (IRS) isoforms IRS-1 and IRS-2 and less so with the IRS-isoform Grb-2 associated binder-1 (Gab-1). In contrast, GLP-1 induced PI 3-K activity mainly in Gab-1 and also in IRS-2 immunoprecipitates, although in an attenuated kinetic. Thus, activation pathways of PKB/Akt by insulin, IGF-1, and GLP-1 converge at the level of IRS-isoforms and PI 3-K inducing differential activation of PKB/Akt. These data indicate an essential role of PKB/Akt in regulation of beta-cell proliferation.
...
PMID:Integrative mitogenic role of protein kinase B/Akt in beta-cells. 1119 29

The serine/threonine kinase protein kinase B (PKB/Akt) has been shown to play a crucial role in the control of diverse and important cellular functions such as cell survival and glycogen metabolism. There is also convincing evidence that PKB plays a role in the insulin-mediated regulation of glucose transport. Furthermore, states of cellular insulin resistance have been shown to involve impaired PKB activation, and this usually coincides with a loss of glucose transport activation. However, evidence to the contrary is also available, and the role of PKB in the control of glucose transport remains controversial. Here we provide an overview of recent findings, discuss the potential importance of PKB in the regulation of glucose transport and metabolism, and comment on future directions.
...
PMID:Protein kinase B (PKB/Akt)--a key regulator of glucose transport? 1125 94

Hyperglycemia is responsible for many of the vascular complications and metabolic derangements seen in diabetes. One potential regulator of the effects of glucose is the hexosamine biosynthesis pathway (HBP). Glutamine: fructose-6-phosphate amidotransferase (GFA), the first and rate-limiting enzyme in this pathway, catalyzes the transfer of an amino group from glutamine to fructose-6-phosphate to form glucosamine-6-phosphate. Overexpression of GFA in rat-1 fibroblasts results in insulin resistance for glycogen synthase (GS) activity, and renders these cells more sensitive to the effects of glucose. Using rat-1 cells, we examine further the mechanisms whereby hexosamines lead to insulin resistance. Insulin stimulated GS activity was found to occur via a PI-3 kinase (PI-3K)-dependent pathway as wortmannin, an inhibitor of PI-3K, blocked insulin's ability to stimulate GS activity. Subsequently, we examined the effects of hexosamines on PI-3K and Akt/PKB activity. Cells were cultured in 1 mM glucose (low glucose, LG), 20 mM glucose (high glucose, HG), or 1 mM glucose plus 3 mM glucosamine (GlcN) for 16--20 h. After treatment with insulin (100 nM) for 5 min, cell extracts were assayed for IRS-1 associated and total PI-3K activity. At LG, insulin increased PI-3K activity by 43%. There was no insulin stimulation of PI-3K activity in cells cultured in HG or GlcN. There was a trend for IRS-1 protein levels to decrease in HG but not GlcN. PI-3K protein levels were not altered by HG or GlcN. Finally PKB activity was assayed. At LG, insulin stimulated PKB activity. Again, both HG and GlcN significantly reduced insulin's ability to stimulate PKB activity. We conclude that the hexosamine-mediated insulin resistance of GS activity seen in rat-1 cells is mediated by hexosamine regulation of PI-3K and PKB.
...
PMID:Glucose-induced insulin resistance of phosphatidylinositol 3'-OH kinase and AKT/PKB is mediated by the hexosamine biosynthesis pathway. 1127 5

The effect of ciprofibrate therapy on plasma lipids and lipoproteins, HDL and LDL subfraction profile, fractional esterification rate of HDL cholesterol (FER(HDL)) and the resistance of LDL and serum lipids to oxidation was studied in 24 males with type 2 diabetes and atherogenic lipoprotein phenotype (ALP). We also examined the effect of ciprofibrate therapy on oxidative DNA damage in peripheral lymphocytes. No differences in glucose, HbA1C and BMI levels were found after three months of ciprofibrate therapy. Ciprofibrate significantly decreased total cholesterol and triglyceride levels by 5.5% and 50% (p = 0.05; 0.001, respectively) and increased HDL-cholesterol levels by 8.5% (p = 0.05). FER(HDL) and LDL subfraction profile were also favorably affected. However, no effect on HDL subclasses was found. There were no statistically significant differences in lipid resistance to oxidation measured in serum and in LDL (lag time and Vmax) before and after therapy. No significant effect of ciprofibrate was found on oxidative DNA damage. The evaluation of the relationship between oxidative damage of purines with lag time in LDL and maximal rate of serum lipid oxidation showed significant correlations after therapy (r = -0.58; 0.47, p = 0.01; 0.05, respectively), but only trends before starting ciprofibrate treatment. Type 2 diabetes mellitus represents a complex metabolic disorder expressed in glucose and lipoprotein disturbances and increased oxidative stress. Ciprofibrate therapy favorably affected major features of lipid abnormalities of diabetic patients, but the level of oxidative stress assessed by in vitro and in vivo methods was not changed. The evaluation of expected logical correlations between the parameters of lipoprotein metabolism, lipid resistance in serum and LDL, and oxidative DNA damage showed that those correlations were more relevant and significant after ciprofibrate treatment and were not related with glucose homeostasis.
...
PMID:Effect of ciprofibrate on lipoprotien metabolism and oxidative stress parameters in patients with type 2 diabetes mellitus and atherogenic lipoprotein phenotype. 1127 13

The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1). Here, we demonstrate that the cultured neonatal cardiomyocyte is not an appropriate model to study the effects of GH because of artifactual loss of GH receptors (GHRs). To circumvent this problem, rat neonatal cardiomyocytes were infected with a recombinant adenovirus expressing the murine GHR. Functional integrity of GHR was suggested by GH-induced activation of the cognate JAK2/STAT5, MAPK, and Akt intracellular pathways in the cells expressing GHR. Although exposure to GH resulted in a significant increase in the size of the cardiomyocyte and increased expression of c-fos, myosin light chain 2, and skeletal alpha-actin mRNAs, there were no significant changes in IGF-1 or atrial natriuretic factor mRNA levels in response to GH stimulation. In this model, GH increased incorporation of leucine, uptake of palmitic acid, and abundance of fatty acid transport protein mRNA. In contrast, GH decreased uptake of 2-deoxy-d-glucose and levels of Glut1 protein. Thus, in isolated rat neonatal cardiomyocytes expressing GHR, GH induces hypertrophy and causes alterations in cellular metabolic profile in the absence of demonstrable changes in IGF-1 mRNA, suggesting that these effects may be independent of IGF-1.
...
PMID:Demonstration of direct effects of growth hormone on neonatal cardiomyocytes. 1130 22

Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidylcholine with subsequent increases in phosphatidic acid (PA) and diacylglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.
...
PMID:Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. 1136 19

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism. We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.
...
PMID:Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. 1139 Mar 60

GLUT-4-containing membranes immunoprecipitated from insulin-stimulated rat skeletal muscle produce the phospholipase D (PLD) product phosphatidic acid. In vitro stimulation of PLD in crude membrane with ammonium sulfate (5 mM) resulted in transfer of GLUT-4 (3.0-fold vs. control) as well as transferrin receptor proteins from large to small membrane structures. The in vitro GLUT-4 transfer could be blocked by neomycin (a PLD inhibitor), and neomycin also reduced insulin-stimulated glucose transport in intact incubated soleus muscles. Furthermore, protein kinase B(beta) (PKB(beta)) was found to associate with the GLUT-4 protein and was transferred to small vesicles in response to ammonium sulfate in vitro. Finally, addition of cytosolic proteins, prepared from basal skeletal muscle, and GTP nucleotides to an enriched GLUT-4 membrane fraction resulted in in vitro transfer of GLUT-4 to small membranes (6.8-fold vs. unstimulated control). The cytosol and nucleotide-induced GLUT-4 transfer could be blocked by neomycin and N-ethylmaleimide. In conclusion, we have developed a cell-free assay that demonstrates in vitro GLUT-4 transfer. This transfer may suggest release of GLUT-4-containing vesicles from donor GLUT-4 membranes involving PLD activity and binding of PKB(beta) to GLUT-4.
...
PMID:GLUT-4 translocation in skeletal muscle studied with a cell-free assay: involvement of phospholipase D. 1150 Mar 17

Osmotic shock induces GLUT4 translocation and glucose uptake through a mechanism independent of PI 3-kinase, but dependent on tyrosine phosphorylation of cellular proteins. To identify the tyrosine phosphorylated proteins required for osmotic shock-stimulated glucose uptake, we examined tyrosine phosphorylation of candidate proteins, and found that the 60-80kDa species including paxillin and the 120-130kDa species including p130Cas, PYK2, FAK and Gab1 were tyrosine-phosphorylated in response to osmotic shock. Inhibition of actin polymerization by cytochalasin D significantly decreased the tyrosine phosphorylation of paxillin, p130Cas, PYK2 and FAK but not Gab1, but had no effect on 2-deoxyglucose (DOG) uptake, suggesting a role for Gab1 in osmotic shock-induced glucose transport. Also, we found that osmotic shock increases the association of phospholipase C-gamma (PLC-gamma) with Gab1 and stimulates tyrosine phosphorylation of PLC-gamma itself. The PLC inhibitor, U73122, inhibited osmotic shock-induced 2-DOG uptake. These results suggest that tyrosine phosphorylation of Gab1 and subsequent recruitment and activation of PLC-gamma may play a role in osmotic shock-induced glucose transport.
...
PMID:Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes. 1150 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---