Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that different agonists increase tyrosine phosphorylation of the focal adhesion related proteins p125(FAK), p130(Cas), and paxillin in different cell types and that tyrosine phosphorylation depends on the integrity of the actin cytoskeleton. Because phosphoinositides are important for the maintenance of the cytoskeleton, the role of phosphoinositides in the tyrosine phosphorylation of these proteins in response to occupancy of m3 muscarinic and CCK(A) receptors has been investigated in pancreatic acini. Addition of carbachol or CCK-8 to pancreatic acini resulted in rapid increases in the tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin. Pretreatment of pancreatic acini with LY294002 or wortmannin resulted in a concentration-dependent inhibition of tyrosine phosphorylation of p125(FAK), p130(Cas), and paxillin stimulated by carbachol or CCK-8. Carbachol- or CCK-8-stimulated tyrosine phosphorylation of these proteins was not inhibited by rapamycin, PD 98059 or SB 203580, and thus it was dissociated from the activation of p70 S6 or MAP kinases. These results indicate that m3 muscarinic and CCK(A) receptor-mediated increase in p125(FAK), p130(Cas), and paxillin tyrosine phosphorylation in pancreatic acini depends on the ability of these cells to synthesise phosphoinositides.
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PMID:A role for phosphoinositides in tyrosine phosphorylation of p125 focal adhesion kinase in rat pancreatic acini. 1070 24

Drug resistance remains a serious limiting factor in the treatment of acute myeloid leukaemia (AML) either at initial presentation or following primary or subsequent relapses. Using specific kinase inhibitors, this study has investigated the contribution of the Ras/PI3-kinase regulated survival pathways to drug resistance and suppression of apoptosis in a cell line derived from AML (HL60). Inhibition of the Raf/MAP-kinase (ERK) pathway with a specific MAP-kinase inhibitor, apigenin did not sensitise HL60 cells to drug-induced apoptosis, indicating a lack of involvement in chemoresistance. In contrast, the PI3-kinase inhibitors, LY294002 and wortmannin, did induce a significant increase in apoptosis in combination with cytotoxic drugs. The contribution of downstream mediators of PI3-kinase, p70S6-kinase and PKB/Akt were then investigated. While inhibition of p70S6-kinase with rapamycin did not increase drug-induced apoptosis, PI3-kinase inhibition resulted in notable dephosphorylation of PKB, suggesting that the PI3-kinase/PKB survival pathway may play a major role in chemoresistance in AML. This pathway has been reported to mediate heterodimer interactions with the proapoptotic regulator, Bad. In contrast to previous studies, we found no evidence of Bad binding to anti-apoptotic Bcl-2, Bcl-XL or McI-1, or of alterations in Bax heterodimers. This suggests that alternative targets of PI3-kinase/PKB, distinct from the Bcl-2 family may be responsible for contributing to survival factor-mediated drug resistance in AML.
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PMID:Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals. 1076 45

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

The effect of insulin on glucose transport, glucose transporter 4 (Glut4) translocation, and intracellular signaling were measured in fat cells from lean and obese Zucker rats of different ages. Insulin-stimulated glucose transport was markedly reduced in adipocytes from old and obese animals. The protein content of Glut4 and insulin receptor substrates (IRS) 1 and 2 were also reduced while other proteins, including the p85 subunit of PI3-kinase, Shc and the MAP kinases (ERK1 and 2) were essentially unchanged. There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old and obese animals. Furthermore, insulin-stimulated translocation of both Glut4 and PKB to the plasma membrane was virtually abolished. The phosphotyrosine phosphatase inhibitor, vanadate, increased the insulin-stimulated upstream signaling including PI3-kinase and PKB activities as well as rate of glucose transport. Thus, the insulin resistance in cells from old and obese Zucker rats can be accounted for by an impaired translocation process, due to signaling defects leading to a reduced activation of PI3-kinase and PKB, as well as an attenuated Glut4 protein content.
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PMID:Insulin resistance in fat cells from obese Zucker rats--evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4. 1083 89

Rat eosinophil survival was prolonged by recombinant rat IL-5 prepared by the baculovirus expression system. The IL-5-induced prolongation of eosinophil survival was dose-dependently inhibited by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that recombinant rat IL-5 activates JAK2 tyrosine kinase, which phosphorylates STAT5, and induces protein synthesis required for the prolongation of rat eosinophil survival.
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PMID:Analysis of the prolongation of rat eosinophil survival induced by recombinant rat interleukin-5. 1086 6

In the present study we have examined the proteins involved in the insulin signaling cascade during and after differentiation of human adipocyte precursor cells and their correlation with glucose uptake. The differentiation of human adipocytes was characterized by a two- to threefold stimulation of glucose transport in response to insulin and a marked increase protein expression for the insulin receptor, IRS-1, GLUT-4, PI 3-kinase, and PKB, with respect to undifferentiated cells. In contrast, there were small changes in the protein expression of IRS-2, and no changes in PKC zeta and MAP kinases, although basal MAP kinase activity and GLUT-1 protein were reduced during differentiation. In conclusion, there are quantitative differences in the regulation of IRS-1 and other proteins during differentiation which may contribute to more efficient insulin signaling leading to glucose uptake in mature fat cells. Alterations in this pattern may reflect or contribute to an insulin-resistant state.
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PMID:Regulation of proteins involved in insulin signaling pathways in differentiating human adipocytes. 1100

PLEASE NOTE: This draft Special Report is an evidence-based analysis of the relative effectiveness of different treatment programs and components of treatment for anorexia nervosa. It does not attempt to address the question as to whether the TEC criteria are met.
Tecnologica MAP Suppl 2000 Jun
PMID:Special report: relative effectiveness of treatment programs and components of treatment for anorexia nervosa. 1106 85

Inhibition of signaling through Ras in BCR-ABL-positive pluripotent K562 cells leads to apoptosis and spontaneous differentiation. However, Ras-induced activation of the mitogen-activated protein kinase ERK has been suggested to play a critical role in either growth or differentiation in different model systems. We studied the role of ERK activation in the growth-promoting and anti-apoptotic effect of Ras and its involvement in hemin-induced nonterminal erythroid differentiation using the BCR-ABL-positive K562 cell line as a model. K562 cells were stably transfected with ERK1 or the dominant inhibitory mutant of ERK1 (ERK1-KR). Overexpression of ERK1-KR inhibited cell growth with an approximately fourfold increase in doubling time and induced apoptosis in K562 cells. Incubation with the MEK1 inhibitor UO126 inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner as well. In the presence of exogenously added hemin, K562 cells differentiate into erythroblasts, as indicated by the production of large amounts of fetal hemoglobin. We examined the activation of MAP kinases during hemin-induced differentiation. The ERK1 and 2 activity increased within 2 h post hemin treatment and remained elevated for 24-48 h. During this time, fetal hemoglobin synthesis also increases from 0.8 to 10 pg/cell. There was no activation of JNK or p38 protein kinases. The hemin-induced accumulation of hemoglobin was inhibited in ERK1-KR overexpressing cells and was enhanced in the wild-type ERK1 transfectants. Our results suggest that ERK activation is involved in both growth and hemin-induced erythroid differentiation in the BCR-ABL-positive K562 cell line.
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PMID:Role of ERK activation in growth and erythroid differentiation of K562 cells. 1126 76

Nitric oxide (NO) can participate in cellular signaling. In this study, monoclonal antibodies against proteins from the growth factor-mediated signalling pathway were used to identify a set of 126-, 56-, 43-, and 40-kDa proteins phosphorylated on tyrosine at NO stimulation of murine fibroblasts overexpressing the human epidermal growth factor receptor. The band corresponding to the 126-kDa protein was FAK. The 56-kDa protein was Src kinase, and the doublet 43- and 40-kDa protein corresponded to the extracellular-regulated MAP kinases (ERK1/ERK2). The effects of NO on focal adhesion complexes were also investigated. FAK was constitutively associated with the adapter protein Grb2 in HER14 cells. Treatment of the cells with the NO donor, sodium nitroprusside, or with EGF did not change this association. We also detected a basal constitutive association of Src kinase with FAK in HER14 cells. In NO-treated cells, this association was stimulated. The doublet 43/40-kDa protein was identical to the ERK1/ERK2 MAP kinases. NO stimulated an increase in ERK1/ERK2 phosphorylation as assessed by a shift in its eletrophoretic mobility and by increased phosphotyrosine immunoreactivity. Furthermore, NO-dependent activation of ERK1/ERK2 depended on the intracellular redox status. Inhibition of glutathione synthesis was necessary to promote activation of the kinases.
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PMID:Nitric oxide stimulates tyrosine phosphorylation of focal adhesion kinase, Src kinase, and mitogen-activated protein kinases in murine fibroblasts. 1128 Dec 84

Recombinant rat interleukin (IL)-5-induced prolongation of rat eosinophil survival in culture was inhibited in a concentration-dependent manner by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A when examined 96 h after incubation. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that the activation of JAK2 tyrosine kinase and protein synthesis are required for the prolongation of rat eosinophil survival induced by recombinant rat IL-5. STAT5 phosphorylation might also participate in the IL-5-induced survival of rat eosinophils.
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PMID:Possible participation of a JAK2 signaling pathway in recombinant rat interleukin-5-induced prolongation of rat eosinophil survival. 1133 6


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