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

Nat Cell Biol. 2009 Feb;11(2):133-42. doi: 10.1038/ncb1822. Epub 2009 Jan 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Enzyme Activation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplasms / enzymology*
  • Neoplasms / genetics*
  • Neoplasms / physiopathology
  • Peptidylprolyl Isomerase / genetics*
  • Peptidylprolyl Isomerase / metabolism*
  • Protein Structure, Tertiary / genetics
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism*
  • Transcriptional Activation / genetics


  • NIMA-Interacting Peptidylprolyl Isomerase
  • NOTCH1 protein, human
  • Receptor, Notch1
  • Amyloid Precursor Protein Secretases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase