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      Roughing up Smoothened: chemical modulators of Hedgehog signaling

      review-article
      1 ,
      Journal of Biology
      BioMed Central

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          Abstract

          Small-molecule antagonists of Hedgehog-pathway signaling, such as cyclopamine, have been known for some time. Now, small-molecule agonists of the Hedgehog pathway have also been identified. The finding that both antagonists and agonists target the protein Smoothened supports the emerging hypothesis that Smoothened may be regulated by endogenous small molecules.

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          Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.

          Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential 'mechanism-based' therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.
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            Small molecule modulation of Smoothened activity.

            Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.
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              Patched acts catalytically to suppress the activity of Smoothened.

              Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.
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                Author and article information

                Journal
                J Biol
                Journal of Biology
                BioMed Central (London )
                1478-5854
                1475-4924
                2002
                6 November 2002
                : 1
                : 2
                : 8
                Affiliations
                [1 ]Institute of Chemistry and Cell Biology, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
                Article
                1475-4924-1-8
                137068
                12437769
                207ea1ba-b687-411d-b042-21acb29010d9
                Copyright © 2002 BioMed Central Ltd
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                Life sciences
                Life sciences

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