Patched acts catalytically to suppress the activity of Smoothened

@article{Taipale2002PatchedAC,
  title={Patched acts catalytically to suppress the activity of Smoothened},
  author={Jussi Taipale and Michael K. Cooper and Tapan Maiti and Philip A. Beachy},
  journal={Nature},
  year={2002},
  volume={418},
  pages={892-896}
}
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… Expand
Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila
TLDR
It is shown that Smo accumulates in the plasma membrane of cells in which Ptc activity is abrogated by Hh but is targeted to the degradative pathway in cells where Ptc is active and is likely to be a cause, rather than a consequence, of Hh signal transduction. Expand
Inhibition of GLI1 gene activation by Patched1.
TLDR
It is shown that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. Expand
Interaction of the Hedgehog and vitamin D receptor signaling pathways in Patched associated cancers
TLDR
The findings that calcitriol inhibits Hh signaling at the level of Smo and reduces tumor growth in murine models for basal cell carcinoma (BCC) and rhabdomyosarcoma (RMS) indicate that calcriol could be the first physiologically-existing Smo inhibitor to be discovered. Expand
Smoothened stimulation by membrane sterols drives Hedgehog pathway activity
TLDR
The crystal structure of active mouse SMO in complex with the SAG21k agonist and a stabilizing intracellular binding nanobody reveals the structural basis of SMO regulation by PTCH1, and suggests a strategy for overcoming clinical resistance to SMO inhibitors. Expand
Smoothened stimulation by membrane sterols drives Hedgehog pathway activity
Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration1. Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinomaExpand
The Hedgehog pathway effector smoothened exhibits signaling competency in the absence of ciliary accumulation.
TLDR
It is demonstrated that Smo supplied with a synthetic agonist or activated with oncogenic mutations can signal without ciliary accumulation, and that cells with compromised ciliary Smo trafficking due to loss of the phosphatidylinositol-4-phosphate 3-kinase (PI3K)-C2α retain transcriptional response to an exogenously supplied Smo agonist. Expand
Patched1 and Patched2 inhibit Smoothened non-cell autonomously
TLDR
A model in which Ptch1/2 mediate secretion of a Smo-inhibitory cholesterol precursor is supported, in which cells with differing Ptch 1/2 status repressed the Hh response and Ptch2/2 mediates non-cell autonomous inhibition. Expand
Characterizing the Structure and Function of the Cytoplasmic Domains of Ptch1
TLDR
It is shown that the intracellular ML and CTD of Ptch1 are dispensable for canonical Hh-signalling, and the deletion of the cytoplasmic “middle loop” domain generates a Ptch 1 mutant that constitutively suppresses Hhsignaling and increases the length of primary cilia. Expand
Structural basis for the recognition of Sonic Hedgehog by human Patched1
TLDR
The cryo–electron microscopy structure of the human receptor for the regulator of development and regeneration shows steroid dependency, and mutational analysis indicates that the interaction between Ptch1 and Hh is steroid-dependent. Expand
Repression of Smoothened by Patched-Dependent (Pro-)Vitamin D3 Secretion
TLDR
Hh activates its signalling cascade by inhibiting Ptch1-dependent secretion of the 3β-hydroxysteroid (pro-)vitamin D3, which establishes Hh as a unique morphogen, because binding of Hh on one cell is capable of activating Hh-dependent signalling cascades on other cells. Expand
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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