Hrs mediates downregulation of multiple signalling receptors in Drosophila

EMBO Rep. 2003 Dec;4(12):1163-8. doi: 10.1038/sj.embor.7400019. Epub 2003 Nov 7.

Abstract

Endocytosis and subsequent lysosomal degradation of activated signalling receptors can attenuate signalling. Endocytosis may also promote signalling by targeting receptors to specific compartments. A key step regulating the degradation of receptors is their ubiquitination. Hrs/Vps27p, an endosome-associated, ubiquitin-binding protein, affects sorting and degradation of receptors. Drosophila embryos mutant for hrs show elevated receptor tyrosine kinase (RTK) signalling. Hrs has also been proposed to act as a positive mediator of TGF-beta signalling. We find that Drosophila epithelial cells devoid of Hrs accumulate multiple signalling receptors in an endosomal compartment with high levels of ubiquitinated proteins: not only RTKs (EGFR and PVR) but also Notch and receptors for Hedgehog and Dpp (TGF-beta related). Hrs is not required for Dpp signalling. Instead, loss of Hrs increases Dpp signalling and the level of the type-I receptor Thickveins (Tkv). Finally, most hrs-dependent receptor turnover appears to be ligand independent. Thus, both active and inactive signalling receptors are targeted for degradation in vivo and Hrs is required for their removal.

MeSH terms

  • Animals
  • Cell Line
  • Down-Regulation
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Endocytosis
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / metabolism
  • ErbB Receptors / metabolism
  • Hedgehog Proteins
  • Larva
  • Ligands
  • Membrane Proteins / metabolism
  • Mutation
  • Phosphoproteins / analysis
  • Phosphoproteins / metabolism*
  • Protein Transport
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Cell Surface / analysis
  • Receptors, Cell Surface / metabolism*
  • Receptors, Notch
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism
  • Ubiquitin / metabolism

Substances

  • Drosophila Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Hedgehog Proteins
  • Ligands
  • Membrane Proteins
  • N protein, Drosophila
  • Phosphoproteins
  • Receptors, Cell Surface
  • Receptors, Notch
  • Transforming Growth Factor beta
  • Ubiquitin
  • dpp protein, Drosophila
  • hepatocyte growth factor-regulated tyrosine kinase substrate
  • hh protein, Drosophila
  • ErbB Receptors
  • Protein-Tyrosine Kinases