P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP.
P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP.
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DOI：
10.1038/cddis.2014.79
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发表时间：
2014-03-20
影响因子：
9
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中科院分区：
文献类型：
--
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ErbB3结合蛋白1(Ebp1)的短亚型P42被认为在许多人类癌症中是一种有效的肿瘤抑制因子，尽管其发挥这种肿瘤抑制活性的机制尚不清楚。在这里，我们报告了P42与磷脂酰肌醇3-激酶(PI3K)的P85亚单位的cSH2结构域相互作用，导致其脂激酶活性的抑制。重要的是，我们发现P42诱导P85亚基的蛋白质降解，并进一步确定HSP70/CHIP复合体是P85的一种新的E3连接酶，负责P85的泛素化和降解。在这个过程中，P42将P85偶联到HSP70/CHIP介导的泛素-蛋白酶体系统(UPS)，从而在体外和体内促进P85水平的降低。因此，P42在癌细胞中的肿瘤抑制作用是由PI3K的P85亚单位的负调控驱动的。
The short isoform of ErbB3-binding protein 1 (Ebp1), p42, is considered to be a potent tumor suppressor in a number of human cancers, although the mechanism by which it exerts this tumor-suppressive activity is unclear. Here, we report that p42 interacts with the cSH2 domain of the p85 subunit of phosphathidyl inositol 3-kinase (PI3K), leading to inhibition of its lipid kinase activity. Importantly, we found that p42 induces protein degradation of the p85 subunit and further identified HSP70/CHIP complex as a novel E3 ligase for p85 that is responsible for p85 ubiquitination and degradation. In this process, p42 couples p85 to the HSP70/CHIP-mediated ubiquitin–proteasomal system (UPS), thereby promoting a reduction of p85 levels both in vitro and in vivo. Thus, the tumor-suppressing effects of p42 in cancer cells are driven by negative regulation of the p85 subunit of PI3K.
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影响因子：
8.2
作者：
Bianchi, M. S.;Hernando-Insua, A.;Lux-Lantos, V. A.
通讯作者：
Lux-Lantos, V. A.
影响因子：
6.2
作者：
Abou Youssif, Tamer;Fahmy, Mona Alam;Sircar, Kanishka
通讯作者：
Sircar, Kanishka
影响因子：
4
作者：
Gurney, Susan M. R.;Forster, Peter;Schwanbeck, Ralf
通讯作者：
Schwanbeck, Ralf
影响因子：
4.8
作者：
Jiang, JH;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C
影响因子：
11.4
作者：
DHAND, R;HARA, K;WATERFIELD, MD
通讯作者：
WATERFIELD, MD