Research ArticleDevelopment

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

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Science Signaling  24 Mar 2015:
Vol. 8, Issue 369, pp. ra30
DOI: 10.1126/scisignal.2005892

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Turned on by cleavage; turned off by methylation and ubiquitination

Notch signaling regulates several processes during development, and aberrant signaling contributes to human disease. The Notch receptor is proteolytically processed, releasing an intracellular fragment called NICD that translocates to the nucleus to regulate gene expression. Hein et al. found that NICD is methylated by the methyltransferase CARM1 at five conserved arginine residues within a domain required for gene regulatory activity. Methylated NICD was targeted for degradation. A mutant form of NICD that could not be methylated was more stable but biologically less active when expressed in frog or zebrafish embryos. Thus, control of Notch signaling involves cleavage to produce the transcriptional regulator and then methylation to target this irreversibly activated product for degradation.

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