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Inhibition of Wnt signalling by Notch via two distinct mechanisms.Acar, Ahmet; email: email@example.com; Hidalgo-Sastre, Ana; Leverentz, Michael K; Mills, Christopher G; Woodcock, Simon; Baron, Martin; Collu, Giovanna M; Brennan, Keith; email: firstname.lastname@example.org (2021-04-27)Notch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. Several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in human cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytic mechanism that requires its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.