The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.
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.
Rustighi
Alessandra
A
Laboratorio Nazionale CIB (LNCIB), Area Science Park, Padriciano 99, 34012 Trieste, Italy.
Tiberi
Luca
L
Soldano
Alessia
A
Napoli
Marco
M
Nuciforo
Paolo
P
Rosato
Antonio
A
Kaplan
Fred
F
Capobianco
Anthony
A
Pece
Salvatore
S
Di Fiore
Pier Paolo
PP
Del Sal
Giannino
G
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase