Chapter

Signaling of Receptor Tyrosine Kinases in the Nucleus

04/2012; ISBN: 978-953-51-0544-2 In book: Current Frontiers and Perspectives in Cell Biology
Source: InTech
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    ABSTRACT: To determine the fate of exogenous epidermal growth factor (EGF) in regenerating liver, 125I-labeled EGF was injected into rat portal veins at various times after 70% hepatectomy. Epidermal growth factor was taken up by the liver remnant at all time points studied (0, 4, 8, 16, and 36 h), but at 8 h after hepatectomy a large quantity was retained by the liver and EGF degradation products appearing in the bile decreased markedly. Electron microscopic autoradiography of the regenerating livers 1 h after injection of 125I-EGF demonstrated that 27% of the grains were associated with hepatocyte nuclei compared to 0.5% in shamoperated controls. There was also a concomitant decrease in grains associated with the lysosomal compartment. Nuclei isolated from regenerating livers exposed to 125I-EGF also demonstrated a three-fold increase in radioactivity compared to nuclei from control livers. Nearly 70% of nuclear radioactivity was precipitable with a specific antibody to EGF, and a small fraction appeared to be part of a high molecular weight complex. These data support the hypothesis that during the pre-S phase of liver regeneration, EGF is translocated to the nucleus rather than to lysosomes, and may participate in the initiation of deoxyribonucleic acid synthesis or alteration of gene expression.
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    ABSTRACT: A number of transmembrane receptors are targeted to the nucleus and convincingly localized therein. However, what remains a conundrum is how these cell-surface receptors end up in the nucleus. In this study, we reported that the transmembrane receptor phosphorylated TrkA was located in a series of carrier vesicles, including ring-like vesicles near the plasma membrane, large core vesicles and small dense core vesicles around the nuclei, as well as in the nucleus in human glioma cell line U251 using immunocytochemistry and immunofluorescence staining. Meanwhile, we also showed that small dense core vesicles budded from large core vesicles, and interacted with the nuclear envelope. Accordingly, our results suggested that such a series of membrane compartments might be involved in the pathway of nuclear translocation of the transmembrane receptor TrkA.
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    ABSTRACT: Transforming growth factor (TGF) alpha, an important mediator of growth stimulation, is known to act via epidermal growth factor receptor (EGF-R) binding in the cell membrane. Here we show by immunohistology, 2-dimensional immunoblotting, and mass spectrometry of nuclear fractions that the pro-protein of wild-type TGF-alpha occurs in hepatocyte nuclei of human, rat, and mouse liver. Several findings show a close association between nuclear pro-TGF-alpha and DNA synthesis. (1) The number of pro-TGF-alpha+ nuclei was low in resting liver and increased dramatically after partial hepatectomy and after application of hepatotoxic chemicals or the primary mitogen cyproterone acetate (CPA); in any case, S phase occurred almost exclusively in pro-TGF-alpha+ nuclei. The same was found in human cirrhotic liver. (2) In primary culture, 7% of hepatocytes synthesized pro-TGF-alpha, which then translocated to the nucleus; 70% of these nuclei subsequently entered DNA replication, whereas only 2% of pro-TGF-alpha- hepatocytes were in S phase. (3) The frequency of hepatocytes coexpressing pro-TGF-alpha and DNA synthesis was increased by the hepatomitogens CPA or prostaglandin E(2) and was decreased by the growth inhibitor TGF-beta1. (4) Treatment with mature TGF-alpha increased DNA synthesis exclusively in pro-TGF-alpha- hepatocytes, which was abrogated by the EGF-R tyrosine kinase inhibitor tyrphostin A25. In conclusion, TGF-alpha gene products may exert mitogenic effects in hepatocytes via 2 different signaling mechanisms: (1) the "classic" pathway of mature TGF-alpha via EGF-R in the membrane and (2) a novel pathway involving the presence of pro-TGF-alpha in the nucleus.
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