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Patched acts catalytically to suppress the activity of Smoothened

J Taipale1, M K Cooper, T Maiti

  • 1Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Nature
|August 23, 2002
PubMed

Insights

Patched (Ptc) protein suppresses Hedgehog (Hh) pathway activity by indirectly inhibiting Smoothened (Smo). Ptc functions as a molecular transporter, crucial for regulating pathway levels in development and cancer.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Research

Background:

  • Mutations in Patched (Ptc) and Smoothened (Smo) activate the Hedgehog (Hh) signaling pathway.
  • Hh pathway dysregulation is linked to human cancers like basal cell carcinoma (BCC) and medulloblastoma.
  • The precise mechanism of Ptc regulation of Smo remains unclear despite genetic evidence.

Purpose of the Study:

  • To elucidate the mechanism by which Patched (Ptc) regulates Smoothened (Smo) activity.
  • To investigate the functional relationship between Ptc and Smo in Hh signaling.
  • To determine the role of Ptc's transmembrane transporter-like structure in its function.

Main Methods:

  • Assessed the physical association between Ptc and Smo in Hh-responsive cells.
  • Quantified the effect of unbound Ptc on Smo activity.
  • Mutagenesis of conserved residues in Ptc, homologous to bacterial transporters, to assess functional impact.

Main Results:

  • Patched (Ptc) and Smoothened (Smo) do not significantly associate within Hh-responsive cells.
  • Free Ptc (unbound by Hh) suppresses Smo activity in a sub-stoichiometric manner, controlling pathway levels.
  • Altering conserved residues in Ptc, analogous to bacterial transporter functions, impairs Ptc's tumor-suppressive activity.

Conclusions:

  • Patched (Ptc) functions indirectly to inhibit Smoothened (Smo) activity, likely via a transmembrane molecular transporter mechanism.
  • Ptc's role as a transporter is critical for regulating Hh pathway activity levels.
  • This mechanism is potentially mediated by modulating the distribution or concentration of a small molecule.

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