title: Hrs mediates downregulation of multiple signalling receptors in Drosophila.
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.
authors: European Molecular Biology Laboratory, Developmental Biology Program, Heidelberg, Germany.
authors: Gáspár
authors: G
authors: Jékely
authors: Pernille
authors: P
authors: Rørth
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D053823:Hedgehog Proteins; D007814:Larva; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis / Q000378:metabolism*; D051880:Receptors, Notch; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D053823:Hedgehog Proteins; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C064196:dpp protein, Drosophila; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C077245:hh protein, Drosophila; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases