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      A comprehensive pathway map of epidermal growth factor receptor signaling

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          Abstract

          The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian cells. Reflecting this importance, it is one of the best-investigated signaling systems, both experimentally and computationally, and several computational models have been developed for dynamic analysis. A map of molecular interactions of the EGFR signaling system is a valuable resource for research in this area. In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. The map is created using CellDesigner software that enables us to graphically represent interactions using a well-defined and consistent graphical notation, and to store it in Systems Biology Markup Language (SBML).

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          Most cited references238

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          CDK inhibitors: positive and negative regulators of G1-phase progression.

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            Stat3 as an oncogene.

            STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.
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              AP-1 function and regulation.

              AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.
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                Author and article information

                Journal
                Mol Syst Biol
                Molecular Systems Biology
                1744-4292
                2005
                25 May 2005
                : 1
                : 2005.0010
                Affiliations
                [1 ] The Systems Biology Institute, Tokyo, Japan
                [2 ] Department of Fundamental Science and Technology, Keio University, Tokyo, Japan
                [3 ] ERATO-SORST Kitano Symbiotic Systems Project, Japan Science and Technology Agency, Tokyo, Japan
                [4 ] Sony Computer Science Laboratories, Inc., Tokyo, Japan
                Author notes
                [a ] The Systems Biology Institute, Suite 6A, 6-31-15 Jingumae, Shibuya, Japan. Tel.: +81 3 5468 1661; Fax: +81 3 5468 1664; E-mail: kitano@ 123456symbio.jst.go.jp
                Article
                msb4100014
                10.1038/msb4100014
                1681468
                16729045
                83a809db-bf31-4b08-b784-36e0987e418c
                Copyright © 2005, EMBO and Nature Publishing Group
                History
                : 23 March 2005
                : 28 April 2005
                Page count
                Pages: 1
                Categories
                Review Article

                Quantitative & Systems biology
                bow-tie structure,epidermal growth factor receptor,graphical notation,comprehensive pathway map,systems biology markup language (sbml)

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