Non-degradative Ubiquitination of the Notch1 Receptor by the E3 Ligase MDM2 activates the Notch Signalling Pathway.

The Notch receptor is necessary for modulating cell fate decisions throughout development and aberrant activation of Notch signalling has been associated with many diseases, including tumorigenesis. The E3 ligase MDM2 plays a role in regulating the Notch signalling pathway through its interaction with NUMB. Here we report that MDM2 can ...
also exert its oncogenic effects on the Notch signalling pathway by directly interacting with the Notch 1 receptor through dual-site binding. This involves both the N-terminal and acidic domains of MDM2 and the RAM and ANK domains of Notch1. Although the interaction between Notch1 and MDM2 results in ubiquitination of Notch1, this does not result in degradation of Notch1 but instead leads to activation of the intracellular domain of Notch1. Further, MDM2 can synergise with Notch1 to inhibit apoptosis and promote proliferation. This highlights yet another target for MDM2-mediated ubiquitination that results in activation of the protein rather than degradation and makes MDM2 an attractive target for drug discovery for both the p53 and Notch signalling pathways.
Biochem. J.
Date: Dec. 20, 2012
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