Research ArticlesNotch Signaling

Ligand-activated Notch undergoes DTX4-mediated ubiquitylation and bilateral endocytosis before ADAM10 processing

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Sci. Signal.  13 Jun 2017:
Vol. 10, Issue 483, eaag2989
DOI: 10.1126/scisignal.aag2989

Ordering the steps to Notch activation

Signaling by the receptor Notch enables cell position to influence cell fate through information conveyed between neighboring cells. Binding of ligand, which is a transmembrane protein on a cell that neighbors the Notch-bearing cell, stimulates Notch cleavage in multiple stages. One cleavage event is mediated by an ADAM family protease and is followed by the cleavage event that generates the biologically active Notch receptor component in the receptor-bearing cell. Chastagner et al. found that ubiquitylation of Notch1 by the E3 ubiquitin ligase DTX4 promoted its internalization in response to ligand binding. Furthermore, ubiquitylation preceded the processing of Notch1 by ADAM10 in an endosomal compartment, and not at the cell surface as is usual for ADAM10 substrates. These results show that the endocytosis of the ligand-bound Notch1 by the ligand-bearing cell is not necessary for the endocytosis of Notch1 by the receptor-bearing cell, as had been previously thought, but rather that both of these endocytosis events are triggered by Notch1 ubiquitylation in the receptor-bearing cell. Because these results also show that the processing of Notch1 by ADAM10 occurs intracellularly, they suggest that it may be necessary for ADAM10 inhibitors to be cell-penetrant to be effective in treating cancers associated with constitutively activated Notch.