Research ArticleBiochemistry

Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling

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Science Signaling  05 Nov 2019:
Vol. 12, Issue 606, eaay2369
DOI: 10.1126/scisignal.aay2369

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How NRARP inhibits Notch signaling

The Notch-regulated ankyrin repeat protein (NRARP) is a feedback inhibitor of Notch signaling. Jarrett et al. found that NRARP inhibited the growth of Notch-dependent, T cell acute lymphoblastic leukemia cells and interacted with two members of the Notch transcriptional activation complex: the Notch intracellular domain (NICD) and the transcription factor RBPJ. The crystal structure of an NRARP-NICD-RBPJ-DNA complex showed that NRARP bound to both NICD and RBPJ through its ankyrin domains. Overexpression of NRARP in cells reduced the abundance of NICD, suggesting that NRARP may promote its degradation. These findings suggest how NRARP inhibits Notch-dependent transcriptional activation and identify the NRARP-NICD-RBPJ interaction as a potentially targetable node to inhibit Notch signaling in disease.

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