The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer
Rustighi, Alessandra * Tiberi, Luca * Soldano, Alessia Napoli, Marco Nuciforo, Paolo Rosato, Antonio Kaplan, Fred Capobianco, Anthony Pece, Salvatore Di Fiore, Pier Paolo Del Sal, Giannino # ×
Macmillan Magazines Ltd.
Nature Cell Biology vol:11 issue:2 pages:133-42
Signalling through Notch receptors requires ligand-induced cleavage to release the intracellular domain, which acts as a transcriptional activator in the nucleus. Deregulated Notch1 signalling has been implicated in mammary tumorigenesis; however the mechanisms underlying Notch activation in breast cancer remain unclear. Here, we demonstrate that the prolyl-isomerase Pin1 interacts with Notch1 and affects Notch1 activation. Pin1 potentiates Notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing Notch1 transcriptional and tumorigenic activity. We found that Notch1 directly induces transcription of Pin1, thereby generating a positive loop. In human breast cancers, we observed a strong correlation between Pin1 overexpression and high levels of activated Notch1. Thus, the molecular circuitry established by Notch1 and Pin1 may have a key role in cancer.