Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein
Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein
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DOI：
10.1074/jbc.c400377200
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发表时间：
2004-10-29
影响因子：
4.8
通讯作者：
Maehama, T
中科院分区：
文献类型：
--
作者：
Okahara, F;Ikawa, H;Maehama, T
肿瘤抑制因子PTEN在调节细胞生长和凋亡的信号通路中起重要作用，在多种肿瘤中失活。在这项研究中，我们发现了一种蛋白质，称为PICT-1（与羧基端1相互作用的蛋白质），它与PTEN的C端结合并调节其磷酸化和周转。通过RNA干扰下调MCF7细胞中的PICT-1可增强PTEN的降解，并伴随其磷酸化降低。PTEN c端肿瘤相关突变体对蛋白质降解非常敏感，它们失去了与PICT-1结合的能力，同时磷酸化水平降低，这表明它们的快速周转是与PICT-1结合受损的结果。我们的研究结果表明，PICT-1是一种促进PTEN磷酸化和PTEN稳定性的PTEN相互作用蛋白。这些发现提示了PTEN转换的一种新的分子机制，这也为c端突变导致PTEN功能丧失提供了解释。
The tumor suppressor PTEN plays an essential role in regulating signaling pathways involved in cell growth and apoptosis and is inactivated in a wide variety of tumors. In this study, we have identified a protein, referred to as PICT-1 ( protein interacting with carboxyl terminus 1), that binds to the C terminus of PTEN and regulates its phosphorylation and turnover. Down-regulation of PICT-1 in MCF7 cells by RNA interference enhances the degradation of PTEN with a concomitant decrease in its phosphorylation. PTEN C-terminal tumor-associated mutants, which are highly susceptible to protein degradation, have lost the ability to bind to PICT-1 along with their reduced phosphorylation, suggesting that their rapid turnover results from impaired binding to PICT-1. Our results identify PICT-1 as a PTEN-interacting protein that promotes the phosphorylation and stability of PTEN. These findings suggest a novel molecular mechanism underlying the turnover of PTEN, which also provides an explanation for the loss of PTEN function due to C-terminal mutations.