Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1863, Issue 1, Pages 166-177Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2015.10.021
Keywords
Notch signaling; Endocytosis; Vesicle trafficking; SARA
Categories
Funding
- Cancer Institute of NSW [06/ECF/1-03]
- National Health and Medical Research Council (NHMRC) [ID1003209]
- NHMRC Senior Research Fellowship [ID1042002]
- Australian Research Council [DP1094119]
- Office of Health and Medical Research, NSW State Government
- Australian Research Council [DP1094119] Funding Source: Australian Research Council
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The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction. (C) 2015 Elsevier B.V. All rights reserved.
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