Dai Xiangping, North Brian J, Inuzuka Hiroyuki
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Oncotarget. 2014 May 30;5(10):3307-15. doi: 10.18632/oncotarget.1939.
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 SCF(Fbw7). 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.
卵巢癌2/失活同源物2（DOC-2/DAB2）相互作用蛋白（DAB2IP）的缺失是一种肿瘤抑制因子，作为一种支架蛋白参与协调调节细胞增殖、存活和凋亡途径。通过组蛋白甲基转移酶EZH2的作用，DAB2IP在多种肿瘤中发生表观遗传下调。尽管DAB2IP在多种肿瘤中存在转录下调，但尚不清楚是否有其他机制导致DAB2IP功能失活。在此，我们证明DAB2IP可通过两种独立机制发生功能下调。首先，我们发现Akt1可使DAB2IP的S847位点磷酸化，这调节了DAB2IP与其效应分子H-Ras和TRAF2之间的相互作用。其次，我们证明DAB2IP可部分通过SCF（Fbw7）泛素-蛋白酶体途径降解。DAB2IP含有两个Fbw7磷酸化降解基序，可受激酶CK1δ调节。因此，我们的数据表明，除了表观遗传下调外，还有另外两条途径可使DAB2IP功能失活。鉴于DAB2IP先前已被确定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DAB2IP来控制癌症发展，因此强调DAB2IP激动剂作为未来抗癌药物开发的潜在治疗方法。
