Hrs mediates downregulation of multiple signalling receptors in Drosophila.
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.
Jékely
Gáspár
G
European Molecular Biology Laboratory, Developmental Biology Program, Heidelberg, Germany.
Rørth
Pernille
P
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
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