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The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

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      Abstract

      Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex ( TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.

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      Most cited references 57

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      The phosphoinositide 3-kinase pathway.

       Lewis Cantley (2002)
      Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.
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        Insulin signalling and the regulation of glucose and lipid metabolism.

        The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.
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          PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

          Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
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            Author and article information

            Affiliations
            [1 ]Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK
            [2 ]School of Life Sciences Research Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, UK
            [3 ]Ludwig Institute for Cancer Research, Royal Free and University College Medical School Branch, London W1W 7BS, England, UK
            [4 ]Department of Biochemistry, University College London, London WC1E 6BT, England, UK
            Author notes

            Address correspondence to Richard F. Lamb, Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK. Tel.: (44) 207-970-6096. Fax: (44) 207-352-5630. email: Richard.Lamb@ 123456icr.ac.uk

            Journal
            J Cell Biol
            The Journal of Cell Biology
            The Rockefeller University Press
            0021-9525
            1540-8140
            19 July 2004
            : 166
            : 2
            : 213-223
            2172316
            200403069
            10.1083/jcb.200403069
            15249583
            Copyright © 2004, The Rockefeller University Press
            Categories
            Research Articles
            Article

            Cell biology

            tsc1-2; pi3k; irs proteins; s6k; insulin

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