Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.
Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.
复制标题
位点特异性蛋白酶体磷酸化控制细胞增殖和肿瘤发生。
DOI：
10.1038/ncb3289
复制
发表时间：
2016-02
影响因子：
21.3
通讯作者：
Dixon JE
中科院分区：
文献类型：
--
作者：
Guo X;Wang X;Wang Z;Banerjee S;Yang J;Huang L;Dixon JE
尽管蛋白酶体降解在细胞中具有根本的重要性，但关于26 S蛋白酶体本身是否以及如何与各种生理过程协调调节却知之甚少。在这里，我们表明，蛋白酶体是动态磷酸化在细胞周期的19 S亚基Rpt 3的Thr 25。CRISPR/Cas9介导的基因组编辑、RNA干扰和生物化学研究表明，阻断Rpt 3-Thr 25磷酸化显著损害蛋白酶体活性并阻碍细胞增殖。通过激酶组范围的筛选，我们已经确定了双特异性酪氨酸调节激酶2（DYRK 2）作为磷酸化Rpt 3-Thr 25的主要激酶，导致底物易位和降解增强。重要的是，Rpt 3-Thr 25单一磷酸化的缺失或DYRK 2的敲除显著抑制小鼠中蛋白酶体成瘾的人乳腺癌细胞的肿瘤形成。这些发现定义了蛋白酶体调节的重要机制，并证明了蛋白酶体磷酸化在调节细胞增殖和肿瘤发生中的生物学意义。
Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during cell cycle at Thr25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumor formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis.