Figure 9

A working model of Notch3 and Kibra co-regulation in breast cancer cells. There is a complex inter-related and inter-dependent correlation between Kibra and Notch3. Loss of Notch3 leads to the decreased Kibra expression at both the transcriptional and protein levels. Downregulated Kibra, through the canonical Hippo kinase cascade, inhibits YAP phosphorylation, contributes to the nuclear accumulation of YAP, initiates target gene transcription and promotes EMT. Furthermore, loss of Kibra leads to downregulation of Notch3 expression. Conversely, ectopically overexpressed Notch3 upregulates Kibra expression, followed by an activated core kinase cassette, inhibited target gene transcription and finally suppressed EMT in breast cancer epithelial cells. In addition, ectopically overexpressed Notch3 upregulates the expression of the apical transmembrane protein Crb (Crumbs), which also interacts with Ex and modulates its localization and stability.