Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity and cellular functions.
Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity and cellular functions.
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DOI：
10.1093/nar/gkac1181
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发表时间：
2022-12-09
影响因子：
14.9
通讯作者：
Dominguez, Cyril
中科院分区：
文献类型：
--
作者：
Malki, Idir;Liepina, Inara;Kogelnik, Nora;Watmuff, Hollie;Robinson, Sue;Lightfoot, Adam;Gonchar, Oksana;Bottrill, Andrew;Fry, Andrew M.;Dominguez, Cyril
Sam 68，也称为KHDRBS 1，是星星蛋白家族的成员，直接将信号转导与转录后基因调控联系起来。Sam 68控制许多致癌蛋白的选择性剪接，其作用受翻译后修饰调节，包括丝氨酸/苏氨酸磷酸化，其在细胞周期的不同阶段不同。然而，这些调制的分子基础和机制在很大程度上仍然未知。在这里，我们结合质谱，核磁共振光谱和细胞生物学技术，提供了一个全面的翻译后修饰映射Sam 68在HEK 293和HCT 116细胞的细胞周期的不同阶段。我们建立了Sam 68特异性磷酸化T33和T317 Cdk 1，并证明这些磷酸化事件减少Sam 68的结合RNA，控制其细胞定位和减少其选择性剪接活性，导致减少诱导凋亡和增加HCT 116细胞的增殖。
Sam68, also known as KHDRBS1, is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, nuclear magnetic resonance spectroscopy and cell biology techniques to provide a comprehensive post-translational modification mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.
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影响因子：
3.7
作者：
Gonze D;Abou-Jaoudé W
通讯作者：
Abou-Jaoudé W
影响因子：
64.8
作者：
Matter, N;Herrlich, P;König, H
通讯作者：
König, H
影响因子：
13.8
作者：
Heyd, Florian;Lynch, Kristen W.
通讯作者：
Lynch, Kristen W.
影响因子：
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Feracci M;Foot JN;Grellscheid SN;Danilenko M;Stehle R;Gonchar O;Kang HS;Dalgliesh C;Meyer NH;Liu Y;Lahat A;Sattler M;Eperon IC;Elliott DJ;Dominguez C
通讯作者：
Dominguez C
影响因子：
14.9
作者：
Daubner GM;Brümmer A;Tocchini C;Gerhardy S;Ciosk R;Zavolan M;Allain FH
通讯作者：
Allain FH