The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking

Curr Biol. 2001 Apr 17;11(8):601-7. doi: 10.1016/s0960-9822(01)00178-6.

Abstract

The Hedgehog (Hh) family of signaling molecules function as organizers in many morphogenetic processes. Hh signaling requires cholesterol in both signal-generating and -receiving cells, and it requires the tumor suppressor Patched (Ptc) in receiving cells in which it plays a negative role. Ptc both blocks the Hh pathway and limits the spread of Hh. Sequence analysis suggests that it has 12 transmembrane segments, 5 of which are homologous to a conserved region that has been identified in several proteins involved in cholesterol homeostasis and has been designated the sterol-sensing domain (SSD). In the present study, we show that a Ptc mutant with a single amino acid substitution in the SSD induces target gene activation in a ligand-independent manner. This mutant Ptc(SSD) protein shows dominant-negative activity in blocking Hh signaling by preventing the downregulation of Smoothened (Smo), a positive effector of the Hh pathway. Despite its dominant-negative activity, the mutant Ptc protein functioned like the wild-type protein in sequestering and internalizing Hh. In addition, we show that Ptc(SSD) preferentially accumulates in endosomes of the endocytic compartment. All these results suggest a role of the SSD of Ptc in mediating the vesicular trafficking of Ptc to regulate Smo activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Binding Sites
  • Biological Transport
  • Drosophila / embryology
  • Drosophila / genetics
  • Drosophila / growth & development
  • Drosophila / metabolism
  • Drosophila Proteins*
  • Endosomes / metabolism
  • Hedgehog Proteins
  • Insect Proteins / genetics
  • Insect Proteins / metabolism*
  • Insect Proteins / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / physiology
  • Mutagenesis
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled*
  • Smoothened Receptor
  • Sterols
  • Up-Regulation
  • Wnt1 Protein

Substances

  • Drosophila Proteins
  • Hedgehog Proteins
  • Insect Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Smoothened Receptor
  • Sterols
  • Wnt1 Protein
  • ptc protein, Drosophila
  • smo protein, Drosophila
  • wg protein, Drosophila
  • hh protein, Drosophila