A Role for Notch Signalling in Breast Cancer and Endocrine Resistance

Figure 1

Basics of Notch signalling pathway. Notch signalling activation occurs via an interaction between DSL ligand and Notch receptor on adjacent cells. This interaction leads to force being applied to the extracellular domain of Notch, as DSL ligand undergoes endocytosis into the signalling cell, leading to a conformational change within the negative regulatory region (NRR). This conformational change exposes a cleavage site (S2) for the ADAM10 and ADAM17 proteases. The extracellularly truncated Notch protein then undergoes cleavage at site 3 (S3), mediated by γ-secretase, which releases the Notch intracellular domain (NICD). Finally, NICD translocates into the nucleus and interacts with the DNA binding protein RBPj and the transcriptional coactivators MAML and p300 to initiate transcription of downstream targets including the Hes and Hey family of genes.