Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

Abstract

Many signalling components are apically restricted in epithelial cells, and receptor localisation and abundance is key for morphogenesis and tissue homeostasis. Hence, controlling apicobasal epithelial polarity is crucial for proper signalling. Notch is a ubiquitously expressed, apically localised receptor, which performs a plethora of functions; therefore, its activity has to be tightly regulated. Here, we show that Drosophila Crumbs, an evolutionarily conserved polarity determinant, prevents Notch endocytosis in developing wings through direct interaction between the two proteins. Notch endocytosis in the absence of Crumbs results in the activation of the ligand-independent, Deltex-dependent Notch signalling pathway, and does not require the ligands Delta and Serrate or γ-secretase activity. This function of Crumbs is not due to general defects in apicobasal polarity, as localisation of other apical proteins is unaffected. Our data reveal a mechanism to explain how Crumbs directly controls localisation and trafficking of the potent Notch receptor, and adds yet another aspect of Crumbs regulation in Notch pathway activity. Furthermore, our data highlight a close link between the apical determinant Crumbs, receptor trafficking and tissue homeostasis.

Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration

“…Pharmacological interventions, such as γ-secreting enzyme inhibitor, Notch-1 ligand, and Akt and Hif-1α inhibitors were used to clarify the specific molecular mechanism. Notch signaling affected the morphogenesis of normal cells, 25 including the differentiation of multipotent progenitor cells, apoptosis, cell proliferation, cell boundary formation, 26 and the occurrence, progression, and metastasis of tumors. 27 Sahlgren reported that hypoxia resulted in elevated expression of Notch downstream genes and HIF-1α, which was stabilized in hypoxia and was found to interact with NICD and enhance its stability.…”

EGFR controls Drosophila tracheal tube elongation by intracellular trafficking regulation

“…Furthermore, our results suggest that the trafficking of Crb and Serp may influence each other, adding an extra layer of coordination to the system. Actually, a role for Crb in regulating endocytic trafficking has been already proposed [64]. Indeed, several reports indicate that polarity proteins are both cargoes and regulators of endocytic recycling [65].…”

Notch3 in Development, Health and Disease

“…This releases Notch intracellular domain (ICD) to translocate to the nucleus where it forms a complex with the transcription factor CBF-1/Suppressor of Hairless/Lag1 (CSL), along with additional cofactors that activate gene transcription ( Figure 2). Additional routes to activation have also been described in both invertebrate and vertebrate models, which are independent of ligand binding [12][13][14][15][16][17][18]. These ligand-independent mechanisms, best characterised in Drosophila, depend on endocytosis of full-length Notch and proteolytic activation in the endosomal and lysosomal membranes ( Figure 2) [13,14,19,20].…”