Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins.
The Notch receptor mediates a short-range signal that regulates many cell fate decisions. The misregulation of Notch has been linked to cancer and to developmental disorders. Upon binding to its ligands, Delta (Dl) or Serrate (Ser), the Notch ectodomain is shed by the action of an ADAM protease. The Notch intracellular domain is subsequently released proteolytically from the membrane by Presenilin and translocates to the nucleus to activate the transcription factor, Suppressor of Hairless. We show in Drosophila that Notch signaling is limited by the activity of two Nedd4 family HECT domain proteins, Suppressor of deltex [Su(dx)] and DNedd4. We rule out models by which Su(dx) downregulates Notch through modulating Deltex or by limiting the adherens junction accumulation of Notch. Instead, we show that Su(dx) regulates the postendocytic sorting of Notch within the early endosome to an Hrs- and ubiquitin-enriched subdomain en route to the late endosome. We propose a model in which endocytic sorting of Notch mediates a decision between its activation and downregulation. Such intersections between trafficking routes may provide key points at which other signals can modulate Notch activity in both normal development and in the pathological misactivation of Notch.
Wilkin
Marian B
MB
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Stopford Road, Manchester M13 9PT, UK.
Carbery
Ann-Marie
AM
Fostier
Maggy
M
Aslam
Hanna
H
Mazaleyrat
Sabine L
SL
Higgs
Jenny
J
Myat
Anna
A
Evans
Dana A P
DA
Cornell
Michael
M
Baron
Martin
M
D000818:Animals; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000502:physiology*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D000075702:Nedd4 Ubiquitin Protein Ligases; D021381:Protein Transport / Q000502:physiology; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology
D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D000075702:Nedd4 Ubiquitin Protein Ligases; C119838:Su(dx) protein, Drosophila; D044767:Ubiquitin-Protein Ligases