Abstract
Author SummaryEstablishment of the correct shape and pattern of tissues within an organism requires the integration of molecular information present in signalling and transcriptional networks and demands delicate exchanges and balances of their activities. A large body of experimental work has revealed close correlations in the activities of two pathways: Notch and Wnt, which suggest the existence of multiple links between them. Notch signalling relies in part upon the activity of the Notch protein, a membrane-bound receptor with a transcription factor domain that can be released from the membrane by proteolytic cleavage. On the other hand Wnt proteins are ligands that trigger changes in the activity of ß-catenin, which is called Armadillo in the fruit fly Drosophila melanogaster. In this study we uncover a previously unknown activity for Notch: endocytosis and trafficking of full length Notch, which targets Armadillo for degradation. This activity of Notch is independent of its ligands, Delta and Serrate, and of its downstream effector, the transcription factor Suppressor of Hairless. We further show that in the absence of Notch, which has been shown to act as a tumor suppressor in mammals, expression of an activated form of Armadillo causes tissue overgrowth and changes in the polarity of cells. Our results suggest that Drosophila Notch can promote the degradation of activated forms of Armadillo and may buffer cells against fluctuations in Wnt signalling activity.
Highlights
The Notch gene of Drosophila encodes a member of a family of conserved single transmembrane receptors with key tasks in the information processing activity of animal cells [1,2,3,4]. They are involved in a wide variety of processes during development but their best characterized function is in the process of lateral inhibition and related events, in which Notch signalling is used to choose between two alternative cell fates in a context dependent manner [4,5,6]
There are some effects on cell fate, e.g., in the notum neural development is observed in regions outside the proneural clusters where Armadillo gain of function or Notch loss of function on their own have little or no effect (Figure S1D–S1F)
There is evidence that the Notch receptor can downregulate the activity of Arm/ß-catenin and that this modulation is important in the homeostasis of Wnt signalling [43,45,48,49,50]
Summary
The Notch gene of Drosophila encodes a member of a family of conserved single transmembrane receptors with key tasks in the information processing activity of animal cells [1,2,3,4]. There are two prominent structural features that define the family: a tandem array of EGF repeats in the extracellular domain that act as docking sites for ligands to trigger and modulate the activity of Notch, and seven ankyrin (ANK) repeats in the intracellular domain that provide a major face for interactions with effectors [7,8,9,10,11,12,13,14]. A number of studies, in Drosophila, suggest that endocytosis and traffic of Notch are required for the generation and activity of Nintra [24,25,26,27,28,29,30,31,32,33]
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