Negative regulation of DAB2IP by Akt and SCFFbw7 pathways.
Negative regulation of DAB2IP by Akt and SCFFbw7 pathways.
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DOI：
10.18632/oncotarget.1939
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发表时间：
2014-05-30
期刊：
影响因子：
--
通讯作者：
Inuzuka H
中科院分区：
文献类型：
--
作者：
Dai X;North BJ;Inuzuka H
卵巢癌缺失2/失能同源物2（DOC-2/DAB 2）相互作用蛋白（DAB 2 IP）是一种肿瘤抑制蛋白，作为支架蛋白参与协调调节细胞增殖、存活和凋亡途径。DAB 2 IP通过组蛋白甲基转移酶EZH 2的作用在多种肿瘤中表观遗传学下调。虽然DAB 2 IP在多种肿瘤中转录下调，但仍不清楚是否有其他机制导致DAB 2 IP的功能失活。在这里，我们表明，DAB 2 IP可以通过两个独立的机制功能下调。首先，我们发现Akt 1可以磷酸化S847上的DAB 2 IP，从而调节DAB 2 IP与其效应分子H-Ras和TRAF 2之间的相互作用。其次，我们证明了DAB 2 IP可以通过泛素-蛋白酶体途径被SCFFbw 7部分降解。DAB 2 IP含有两个Fbw 7磷酸降解决定子基序，其可由激酶CK 1 δ调节。因此，我们的数据表明，除了表观遗传下调，两个额外的途径可以发挥作用的ADAB 2 IP。鉴于DAB 2 IP先前已被确定为在肿瘤发生和转移中具有直接因果作用，我们的数据表明，多种途径可能通过DAB 2 IP来控制癌症的发展，因此突出了DAB 2 IP激动剂作为未来抗癌药物开发的潜在治疗方法。
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor that serves as a scaffold protein involved in coordinately regulating cell proliferation, survival and apoptotic pathways. DAB2IP is epigenetically down-regulated in a variety of tumors through the action of the histone methyltransferase EZH2. Although DAB2IP is transcriptionally down-regulated in a variety of tumors, it remains unclear if other mechanisms contribute to functional inactivation of DAB2IP. Here we demonstrate that DAB2IP can be functionally down-regulated by two independent mechanisms. First, we identified that Akt1 can phosphorylate DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Second, we demonstrated that DAB2IP can be degraded in part through ubiquitin-proteasome pathway by SCFFbw7. DAB2IP harbors two Fbw7 phosho-degron motifs, which can be regulated by the kinase, CK1δ. Our data hence indicate that in addition to epigenetic down-regulation, two additional pathways can functional inactivate DAB2IP. Given that DAB2IP has previously been identified to possess direct causal role in tumorigenesis and metastasis, our data indicate that a variety of pathways may pass through DAB2IP to govern cancer development, and therefore highlight DAB2IP agonists as potential therapeutic approaches for future anti-cancer drug development.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
DOI：
10.1016/j.bbamcr.2013.02.028
发表时间：
2014-01
影响因子：
5.1
作者：
Bassermann, Florian;Eichner, Ruth;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
2
作者：
Goncharuk, Viktor N;del-Rosario, Arthur;Ross, Jeffrey S
通讯作者：
Ross, Jeffrey S
DOI：
10.1073/pnas.0908458106
发表时间：
2009-11-24
影响因子：
11.1
作者：
Xie, Daxing;Gore, Crystal;Hsieh, Jer-Tsong
通讯作者：
Hsieh, Jer-Tsong
影响因子：
4.8
作者：
Wang, Z;Tseng, CP;Hsieh, JT
通讯作者：
Hsieh, JT