Endocytic internalization routes required for delta/notch signaling.
The internalization of transmembrane receptors from the cell surface plays a central role in signal regulation. Receptor internalization can occur through different routes; however, because of the difficulty in selectively blocking these routes in vivo, their roles in signaling are poorly understood. Here we use null mutations in Drosophila dynamin, clathrin, and AP-2 adaptor subunits to analyze internalization requirements for the Delta ligand and its receptor, Notch. Bulk Notch is internalized via AP-2-dependent endocytosis, but signaling by Notch requires AP-2-independent clathrin-dependent endocytosis, highlighting a distinction between Notch endocytic routes required for degradation versus signaling activation. Signaling by Delta requires dynamin, but whether this generates a pulling force of Delta on Notch or allows for Delta entry into a recycling pathway to gain signaling competence is widely debated. Surprisingly, we show that signaling by Delta in germline cells can occur by clathrin-independent endocytosis, when endosomal entry is blocked, and when activity of Rab11 or its effectors is reduced, suggesting that Delta need not pass through a recognized recycling pathway to achieve signaling competence. The absolute requirement for dynamin-dependent endocytosis but not endosomal entry or Rab11 activity supports "pulling force" rather than "recycling" models for Delta activation.
Windler
Sarah L
SL
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA.
Bilder
David
D
D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D002966:Clathrin / Q000235:genetics / Q000502:physiology; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D034281:Dynamins / Q000235:genetics / Q000502:physiology; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D017344:Genes, Insect; D005816:Genetic Complementation Test; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology*; D009154:Mutation; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction
D033962:Adaptor Protein Complex 2; D002966:Clathrin; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C064045:delta protein; D034281:Dynamins; C439628:shi protein, Drosophila