Pin 1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC
Pin 1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC
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DOI：
10.1038/ncb0901-793
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发表时间：
2001-09-01
影响因子：
21.3
通讯作者：
Lu, KP
中科院分区：
文献类型：
--
作者：
Ryo, A;Nakamura, M;Lu, KP
丝氨酸或苏氨酸残基的磷酸化(Ser/Thr-Pro)是一种关键的调节机制，某些磷酸化的Ser/Thr-Pro键的构象受Pro异构酶Pin1的特异性调节。虽然Pin1的抑制会诱导细胞凋亡，但Pin1在人类肿瘤的一个亚群中显著过表达。在这里，我们发现Pin1通过干扰其与腺瘤性息肉病结肠蛋白(APC)的相互作用来调节β-连环蛋白的周转和亚细胞定位。差异显示屏幕显示，Pin1增加了几个β-连环素目标基因的转录，包括那些编码细胞周期蛋白D1和c-Myc的基因。在体外，对Pin1水平的调控会影响β-连环蛋白的稳定性。此外，β-连环蛋白水平在Pin1缺陷小鼠中降低，但在人类乳腺癌中升高，并与Pin1过度表达相关。Pin1直接与β-连环蛋白中APC结合部位附近的磷酸化Ser-Pro基序结合，抑制其与APC的相互作用，增加其移位到细胞核内。因此，Pin1是一种新的β-连环蛋白信号调节因子，它的过度表达可能有助于在乳腺癌等肿瘤中上调β-连环蛋白，在乳腺癌中，APC或β-连环蛋白突变并不常见。
Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta -catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-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 but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta -catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta -catenin signalling and its overexpression might contribute to the upregulation of beta -catenin in tumours such as breast cancer, in which APC or beta -catenin mutations are not common.