The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer

Alessandra Rustighi, Luca Tiberi, Alessia Soldano, Marco Napoli, Paolo Nuciforo, Antonio Rosato, Fred Kaplan, Anthony Capobianco, Salvatore Pece, Pier Paolo Di Fiore, Giannino Del Sal

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Abstract

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 γ-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.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalNature Cell Biology
Volume11
Issue number2
DOIs
Publication statusPublished - 2009

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., Kaplan, F., Capobianco, A., Pece, S., Di Fiore, P. P., & Del Sal, G. (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology, 11(2), 133-142. https://doi.org/10.1038/ncb1822