The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog - PubMed (original) (raw)
. 2001 Sep 21;276(38):35847-53.
doi: 10.1074/jbc.M103992200. Epub 2001 Jul 18.
Affiliations
- PMID: 11461910
- DOI: 10.1074/jbc.M103992200
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The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog
C Oberg et al. J Biol Chem. 2001.
Free article
Abstract
The Caenorhabditis elegans sel-10 protein is structurally similar to E3 ubiquitin ligases and is a negative regulator of Notch (lin-12) and presenilin signaling. In this report, we characterize the mammalian Sel-10 homolog (mSel-10) and analyze its effects on Notch signaling. We find that mSel-10 localizes to the cell nucleus, and that it physically interacts with the Notch 1 intracellular domain (IC) and reduces Notch 1 IC-mediated activation of the HES 1 promoter. Notch 1 IC is ubiquitinated by mSel-10, and ubiquitination requires the presence of the most carboxyl-terminal region of the Notch IC, including the PEST domain. In the presence of the proteasome inhibitor MG132, the amount of Notch 1 IC and its level of ubiquitination are increased. Interestingly, this accumulation of Notch 1 IC in the presence of MG132 is accompanied by decreased activation of the HES 1 promoter, suggesting that ubiquitinated Notch 1 IC is a less potent transactivator. Finally, we show that mSel-10 itself is ubiquitinated and degraded by the proteasome. In conclusion, these data reveal the importance of ubiquitination and proteasome-mediated degradation for the activity and turnover of Notch ICs, and demonstrate that mSel-10 plays a key role in this process.
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