Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain

Eric H. Schroeter, Jeffrey A. Kisslinger and Raphael Kopan ()
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Eric H. Schroeter: Washington University
Jeffrey A. Kisslinger: Washington University
Raphael Kopan: Washington University

Nature, 1998, vol. 393, issue 6683, 382-386

Abstract: Abstract Notch proteins are ligand-activated transmembrane receptors involved in cell-fate selection throughout development1,2,3. No known enzymatic activity is contained within Notch and the molecular mechanism by which it transduces signals across the cell membrane is poorly understood. In many instances, Notch activation results in transcriptional changes in the nucleus through an association with members of the CSL family of DNA-binding proteins (where CSL stands for CBF1, Su(H), Lag-1)1,2,3,4. As Notch is located in the plasma membrane and CSL is a nuclear protein, two models have been proposed to explain how they interact (Fig. 1) . The first suggests that the two interact transiently at the membrane1,5,6,7. The second postulates that Notch is cleaved by a protease, enabling the cleaved fragment to enter the nucleus6,8,9,10,11,12,13,14. Here we show that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL. Very small amounts of NICD are active, explaining why it is hard to detect in the nucleus in vivo. We also show that it is ligand binding that induces release of NICD. Figure 1 Different predictions are made by two models of Notch signalling. a, Models not invoking processing propose that interactions between Notch and CSL at the membrane may be sufficient to transduce a signal. Thus, ligand-regulated NICD release is not expected to be necessary for signalling. b, The processing model suggests that Notch signalling requires the release of NICD, which is capable of direct interaction with CSL in the nucleus, to turn on transcription of target genes. This model predicts that NICD release is regulated by ligand binding and that blocking proteolysis interferes with signalling. Notch-1 domain symbols as in Fig. 2.

Date: 1998
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DOI: 10.1038/30756

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