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)

Hyperinsulinemia has been shown to be associated with diabetic angiopathy. Migration and proliferation of vascular smooth muscle cells (VSMC) are the processes required for the development of atherosclerosis. In this study, we attempted to determine whether insulin affects mitogenic signaling induced by platelet-derived growth factor (PDGF) in a rat VSMC cell line (A10 cells). PDGF stimulated DNA synthesis which was totally dependent on Ras, because transfection of dominant negative Ras resulted in complete loss of PDGF-stimulated DNA synthesis. Initiation of DNA synthesis was preceded by activation of Raf-1, MEK and MAP kinases (Erk 1 and Erk2). Treatment of the cells with PD98059, an inhibitor of MAPK kinase (MEK) attenuated but did not abolish PDGF-stimulated DNA synthesis, suggesting that MAPK is required but not essential for DNA synthesis. PDGF also stimulated phosphorylation of protein kinase B (Akt/PKB) and p70 S6Kinase (p70S6K) in a wortmannin-sensitive manner. Rapamycin, an inhibitor of p70S6K, markedly suppressed DNA synthesis. Low concentrations of insulin (1-10 nmol/l) alone showed little mitogenic activity and no significant effect on MAPK activity. However, the presence of insulin enhanced both DNA synthesis and MAPK activation by PDGF. The enhancing effect of insulin was not seen in cells treated with PD98059. Insulin was without effect on PDGF-stimulated activations of protein kinase B (Akt/PKB) and p70S6K. We conclude that insulin, at pathophysiologically relevant concentrations, potentiates the PDGF-stimulated DNA synthesis, at least in part, by potentiating activation of the MAPK cascade. These results are consistent with the notion that hyperinsulinemia is a risk factor for the development of atherosclerosis.
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PMID:Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. 1199 Nov 99

This review postulates and presents recent evidence that insulin resistance is initiated in the adipose tissue and also suggests that the adipose tissue may play a pivotal role in the induction of insulin resistance in the muscles and the liver. Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. However, insulin-stimulated glucose transport and glycogen synthesis are markedly reduced. Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. In addition, GLUT4 expression is markedly reduced in these cells, similar to what is seen in diabetic cells. The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. It is proposed that insulin resistance and/or its effectors is initiated in fat cells and that this may secondarily encompass other target tissues for insulin, including the impaired glucose transport in the muscles.
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PMID:Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance--is insulin resistance initiated in the adipose tissue? 1208 Apr 41

Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. The regulation of these associations in situations of altered insulin receptor substrate-1 (IRS-1) phosphorylation was not yet investigated. In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism.
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PMID:Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. 1216 18

The mechanisms by which insulin-like growth factor I (IGF-I) and insulin regulate eukaryotic initiation factor (eIF)4F formation were examined in the ovine fetus. Insulin infusion increased phosphorylation of eIF4E-binding protein (4E-BP1) in muscle and liver. IGF-I infusion did not alter 4E-BP1 phosphorylation in liver. In muscle, IGF-I increased 4E-BP1 phosphorylation by 27%; the percentage in the gamma-form in the IGF-I group was significantly lower than that in the insulin group. In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased eIF4E. eIF4G binding in muscle, but only insulin decreased the amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I increased eIF4E. eIF4G binding. Insulin increased the phosphorylation of p70 S6 kinase (p70(S6k)) in both muscle and liver and protein kinase B (PKB/Akt) in muscle, two indicative signal proteins in the phosphatidylinositol (PI) 3-kinase pathway. IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on p70(S6k) phosphorylation in muscle or liver. We conclude that insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E. eIF4G binding in muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70(S6k) pathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70(S6k) pathway.
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PMID:IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus. 1216 54

Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by defect of T- and B-cell immunity. In many cases of autosomal recessive SCID, thus far described, the molecular alteration involves genes encoding for molecules that participate in the signal transduction. We report on a patient affected by a combined immunodeficiency, characterized by severe T-cell functional impairment, in spite of a close to normal number of circulating mature type T and B cells. NK cells were absent. Associated with the immunodeficiency, this patient also showed short stature characterized by very low growth velocity, delayed bone age and absence of increase of the plasma levels of Insulin growth factor-I (IGF-I) after growth hormone (GH) in vivo stimulation indicating peripheral hyporesponsiveness to GH. Evaluation of the protein tyrosine phosphorylation events occurring following either T-cell receptor (TCR) or GH receptor (GHR) triggering revealed striking abnormalities. No molecular alteration of GHR gene was found, thus suggesting the presence of postreceptorial blockage. Mutational screening and expression analysis failed to reveal any molecular alteration of JAK2 and STAT 5 A/B genes thus ruling out the involvement of these genes in the pathogenesis of this form of SCID. Mutational analysis of IL2Rgamma chain gene revealed the presence of a L183S missense mutation, thus indicating an atypical and a more complex clinical presentation of this X-linked form of SCID. At our knowledge, this is the first report on the GH hyporesponsiveness in this disease.
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PMID:Atypical X-linked SCID phenotype associated with growth hormone hyporesponsiveness. 1219 92

Insulin rapidly stimulates the tyrosine kinase activity of its receptor, resulting in the phosphorylation of insulin receptor substrates (IRS), which in turn associates and activates PI 3-kinase, leading to an increase in glucose uptake. Phosphorylation of IRS proteins and activation of downstream kinases by insulin are transient and the mechanisms for the subsequent downregulation of their activity are largely unknown. We report here that the insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase association to IRS-1 were strongly sustained by the proteasome inhibitors, MG132 and lactacystin. In contrast, no effect was detected on the insulin receptor and IRS-2 tyrosine phosphorylation. Interestingly, lactacystin also preserved PKB activation and insulin-induced glucose uptake. In contrast, calpeptin, a calpain inhibitor, was ineffective. Tyrosine phosphatase assays were also performed, showing that lactacystin was not functioning directly as a tyrosine phosphatase inhibitor "in vitro." In conclusion, proteasome inhibitors can regulate the tyrosine phosphorylation of IRS-1 and the downstream insulin signaling pathway, leading to glucose transport.
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PMID:Proteasome inhibitors regulate tyrosine phosphorylation of IRS-1 and insulin signaling in adipocytes. 1220 9

Summary. Insulin is known to inhibit glucose-6-phosphatase gene expression through PI 3-kinase/PKB mediated phosphorylation and inactivation of the forkhead transcription factor FKHR, which is a potent transactivator of the glucose-6-phosphatase gene. To study the function and regulation of the transcription factor FKHR in hepatic cells, we constructed a hydroxytamoxifen-inducible version of FKHR by fusing a part of the hormone binding domain of the estrogen receptor (ER) to the C-terminus of FKHR (FKHR-ER). In HepG2-cells transiently transfected with plasmids encoding the FKHR-ER fusion protein and a glucose-6-phosphatase reporter construct, hydroxytamoxifen induced a marked induction of glucose-6-phosphatase promoter activity, whereas no effect was observed in control cells. We next generated a H4IIEC3 rat hepatoma cell line stably expressing both FKHR-ER and a glucose-6-phosphatase promoter-based reporter construct. After 2h stimulation with hydroxytamoxifen, the promoter activity was stimulated 3-5 fold, and continued to increase up to 100-fold after 15 h. The response was half maximal at 0.5 microM hydroxytamoxifen. Insulin (1 nM) decreased the hydroxytamoxifen induced promoter activity by about 70% of the maximal response. This cell system can be used for (1) the identification of FKHR dependent genes and for (2) high throughput screening (HTS) of agents affecting the activity of FKHR and its regulation by insulin. Abbreviations used: FKHR, forkhead in rhabdomyosarcoma; G6Pase, glucose-6-phosphatase; PKB, protein kinase B; PI 3-kinase, phosphatidyl-inositol 3-kinase; IRU, insulin-responsive unit; Tx, 4-hydroxytamoxifen, ER, estrogen receptor; HBD, hormone binding domain
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PMID:Construction and characterization of a conditionally active construct of the insulin-regulated forkhead transcription factor FKHR. 1237 35

Insulin plays an important role in muscle cell survival and proliferation. However, there is no report showing the role of insulin in spreading of muscle cells. In the present report, we showed that insulin enhances muscle cell spreading concomitant with enhanced tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. Moreover, insulin can stimulate the cell spreading even in presence of integrin alpha5 blockers although to a lesser extent as compared to control. Cell adhesion was not dependent on insulin and serum, and decreased in presence of integrin blockers. We found direct association of FAK with affinity purified insulin receptors using in vitro kinase assay. The increase in FAK tyrosine phosphorylation was associated with increase in its kinase activity and further supported by increased phosphotyrosine accumulation on focal adhesions and increased membrane localization of FAK after stimulation by insulin. Moreover, insulin-mediated muscle cell spreading was dependent upon phosphatidylinositol 3-kinase (PI 3-kinase) activity. PI 3-kinase activity was found to be associated with FAK and the FAK associated PI 3-kinase activity enhanced when cells were plated in presence of insulin. We also observed activation of MAP kinases, i.e., ERK-1/-2 during insulin mediated muscle cell spreading. In conclusion, FAK, PI 3-kinase, and MAP kinase are important components of pathway(s) that regulate insulin stimulated muscle cell spreading.
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PMID:Insulin stimulates spreading of skeletal muscle cells involving the activation of focal adhesion kinase, phosphatidylinositol 3-kinase and extracellular signal regulated kinases. 1238 96

The expression of the plasminogen activator inhibitor-1 (PAI-1) gene is enhanced by insulin both in vivo and in various cell types. Because insulin exerts a number of its biologic activities via the phosphatidylinositol 3-kinase and protein kinase B (PI3K/PKB) signaling pathway, it was the aim of the present study to investigate the role of the PI3K/PKB pathway in the expression of the PAI-1 gene and to identify the insulin responsive promoter sequences. It was shown that the induction of PAI-1 mRNA and protein expression by insulin and mild hypoxia could be repressed by the PI3K inhibitor wortmannin. Overexpression of a constitutively active PKB led to induction of PAI-1 mRNA expression and of luciferase (Luc) activity from a gene construct containing 766 bp of the rat PAI-1 promoter. Mutation of the hypoxia response elements (HRE-1 and HRE-2) in rat PAI-1 promoter, which could bind hypoxia inducible factor-1 (HIF-1), abolished the induction of PAI-1 by insulin and PKB. Insulin and the constitutive active PKB also induced Luc expression in cells transfected with the pGl3EPO-HRE Luc construct, containing 3 copies of the HRE from the erythropoietin gene in front of the SV40 promoter. Furthermore, insulin and the active PKB enhanced all 3 HIF alpha-subunit protein levels and HIF-1 DNA-binding activity, as shown by electrophoretic mobility shift assays (EMSAs). Thus, the insulin-dependent activation of the PAI-1 gene expression can be mediated via the PI3K/PKB pathway and the transcription factor HIF-1 binding to the HREs in the PAI-1 gene promoter.
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PMID:Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes. 1239 31

Insulin-like growth factor-binding protein-3 (IGFBP-3) is inhibitory to the growth of many breast cancer cells in vitro; however, a high level of expression of IGFBP-3 in breast tumors correlates with poor prognosis, suggesting that IGFBP-3 may be associated with growth stimulation in some breast cancers. We have shown previously in MCF-10A breast epithelial cells that chronic activation of Ras-p44/42 mitogen-activated protein (MAP) kinase confers resistance to the growth-inhibitory effects of IGFBP-3 (Martin, J. L., and Baxter, R. C. (1999) J. Biol. Chem. 274, 16407-16411). Here we show that, in the same cell line, IGFBP-3 potentiates DNA synthesis and cell proliferation stimulated by epidermal growth factor (EGF), a potent activator of Ras. A mutant of IGFBP-3, which fails to translocate to the nucleus and has reduced ability to cell-associate, similarly enhanced EGF action in these cells. By contrast, the structurally related IGFBP-5, which shares many functional features with IGFBP-3, was slightly inhibitory to DNA synthesis in the presence of EGF. IGFBP-3 primes MCF-10A cells to respond to EGF because pre-incubation caused a similar degree of EGF potentiation as co-incubation. In IGFBP-3-primed cells, EGF-stimulated EGF receptor phosphorylation at Tyr-1068 was increased relative to unprimed cells, as was phosphorylation and activity of p44/42 and p38 MAP kinases, but not Akt/PKB. Partial blockade of the p44/42 and p38 MAP kinase pathways abolished the potentiation by IGFBP-3 of EGF-stimulated DNA synthesis. Collectively, these findings indicate that IGFBP-3 enhances EGF signaling and proliferative effects in breast epithelial cells via increased EGF receptor phosphorylation and activation of p44/42 and p38 MAP kinase signaling pathways.
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PMID:Insulin-like growth factor-binding protein-3 potentiates epidermal growth factor action in MCF-10A mammary epithelial cells. Involvement of p44/42 and p38 mitogen-activated protein kinases. 1243 18


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