A. Ryo et al., Pin 1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC, NAT CELL BI, 3(9), 2001, pp. 793-801
Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr
-Pro) is a key regulatory mechanism, and the conformation of certain phosph
orylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomeras
e Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingl
y overexpressed in a subset of human tumours. Here we show that Pin1 regula
tes beta -catenin turnover and subcellular localization by interfering with
its interaction with adenomatous polyposis coli protein (APC). A different
ial-display screen reveals that Pin1 increases the transcription of several
beta -catenin target genes, including those encoding cyclin D1 and c-Myc.
Manipulation of Pin1 levels affects the stability of beta -catenin in vitro
. Furthermore, beta -catenin levels are decreased in Pin1-deficient mice bu
t are increased and correlated with Pin1 overexpression in human breast can
cer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-bin
ding site in beta -catenin, inhibits its interaction with APC and increases
its translocation into the nucleus. Thus, Pin1 is a novel regulator of bet
a -catenin signalling and its overexpression might contribute to the upregu
lation of beta -catenin in tumours such as breast cancer, in which APC or b
eta -catenin mutations are not common.