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  • 1
    Keywords: RECEPTOR ; CELLS ; GROWTH ; Germany ; INHIBITION ; KINASE ; TYROSINE KINASE ; DIFFERENTIATION ; MECHANISM ; CONTRAST ; PHOSPHORYLATION ; signal transduction ; treatment ; SIGNAL ; ASSAY ; SIGNAL-TRANSDUCTION ; CRYSTAL-STRUCTURE ; Jun ; RECEPTORS ; OXIDATIVE STRESS ; insulin ; INSULIN-RECEPTOR ; TYROSINE KINASES ; SUBSTRATE ; ASSAYS ; INDUCED ACTIVATION ; FRAGMENT ; low dose ; ARSENIC TRIOXIDE ; IGF-1 receptor ; insulin receptor
    Abstract: IGF-1 receptor (IGF1R) is a transmembrane tyrosine kinase, which is indispensable for cellular growth and differentiation. Using a recombinant GST-tagged cytosolic fragment of IGF1R (GST-IGFK), we now show that oxidation by low doses (50 mu M) of hydrogen peroxide markedly inhibits maximum phosphate incorporation in autophosphorylation and substrate phosphorylation assays. A similar inhibition was observed on the activity of intact IGF1R after treatment of T-47D cells. These results are in sharp contrast to the positive influence of hydrogen peroxide on the highly homologous insulin receptor kinase, which was assayed for comparison. This reciprocal influence of physiologically relevant doses of hydrogen peroxide may have important implications on signal transduction of the closely related receptors for insulin and IGF-1
    Type of Publication: Journal article published
    PubMed ID: 16805964
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  • 2
    Keywords: EXPRESSION ; carcinoma ; Germany ; human ; KINASE ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; liver ; NEW-YORK ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TRANSDUCTION ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; CONTRAST ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; antibodies ; antibody ; FORM ; TRANSCRIPTION FACTORS ; DECREASE ; genetics ; SIGNAL-TRANSDUCTION ; MUSCLE ; Jun ; DEGRADATION ; SKELETAL-MUSCLE ; ATROPHY ; pancreatic cancer ; heredity ; REGULATOR ; REGULATORS ; BIOPSY ; ANIMAL-MODELS ; CHAIN ; pancreas ; RE ; PANCREATIC-CANCER ; INCREASE ; TUMORIGENESIS ; HEAVY ; PROTEIN-SYNTHESIS ; WEIGHT ; LEVEL ; PHOSPHATIDYLINOSITOL 3-KINASE ; ANIMAL-MODEL ; USA ; LOSSES ; cachexia ; animal ; ACTIN ; animal model ; BIOPSIES ; comparison ; HYPERTROPHY ; FOXO TRANSCRIPTION FACTORS ; Skeletal muscle ; UBIQUITIN LIGASES
    Abstract: In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation
    Type of Publication: Journal article published
    PubMed ID: 17333095
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  • 3
    Keywords: RECEPTOR ; CELLS ; COMBINATION ; Germany ; KINASE ; SITE ; DOMAIN ; PHOSPHORYLATION ; OBESITY ; CRYSTAL-STRUCTURE ; SKELETAL-MUSCLE ; insulin ; signaling ; ABSENCE ; molecular ; HYDROGEN-PEROXIDE ; regulation ; CREATINE SUPPLEMENTATION ; interaction ; ENHANCEMENT ; REDOX REGULATION ; KINASE-ACTIVITY ; MUTANTS ; insulin signaling ; HYDROGEN ; TYROSINE-PHOSPHATASE 1B ; INTACT-CELLS ; molecular modeling ; CYSTEINE RESIDUES ; INDUCED ACTIVATION
    Abstract: Insulin signaling requires autophosphorylation of the insulin receptor kinase (IRK) domain. Using purified recombinant IRK fragments and the isolated intact insulin receptor, we show here that autophosphorylation is inhibited by ADP and that this effect is essentially reversed by hydrogen peroxide. Autophosphorylation was inhibited by hydrogen peroxide (60 mum) in the absence of ADP but enhanced in the presence of inhibitory concentrations of ADP (67 mum). Enhancement by hydrogen peroxide required direct interaction of hydrogen peroxide with the kinase domain and was not seen in insulin receptor mutants C1245A and C1308A. A similar enhancement was obtained in intact cells in the absence of insulin upon treatment with 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea, indicating that IRK activity can be alternatively enhanced by a shift in the thiol/disulfide redox status. Molecular modeling of the IRK domain indicated that the ATP-binding site becomes distorted after releasing the nucleotide unless the IRK domain is oxidatively derivatized at Cys(1245). Recent clinical studies suggest that these effects may play a role in obesity due to the fact that cytoplasmic creatine kinase in combination with phosphocreatine normally ensures rapid removal of ADP in muscle cells but not in fat cells
    Type of Publication: Journal article published
    PubMed ID: 15563471
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