Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
Biochem J. 2018 Feb 14;475(3):677-690. doi: 10.1042/BCJ20170672.
The splicing of mRNA is dependent on serine-arginine (SR) proteins that are mobilized from membrane-free, nuclear speckles to the nucleoplasm by the Cdc2-like kinases (CLKs). This movement is critical for SR protein-dependent assembly of the macromolecular spliceosome. Although CLK1 facilitates such trafficking through the phosphorylation of serine-proline dipeptides in the prototype SR protein SRSF1, an unrelated enzyme known as SR protein kinase 1 (SRPK1) performs the same function but does not efficiently modify these dipeptides in SRSF1. We now show that the ability of SRPK1 to mobilize SRSF1 from speckles to the nucleoplasm is dependent on active CLK1. Diffusion from speckles is promoted by the formation of an SRPK1-CLK1 complex that facilitates dissociation of SRSF1 from CLK1 and enhances the phosphorylation of several serine-proline dipeptides in this SR protein. Down-regulation of either kinase blocks EGF-stimulated mobilization of nuclear SRSF1. These findings establish a signaling pathway that connects SRPKs to SR protein activation through the associated CLK family of kinases.
mRNA 的剪接依赖于丝氨酸-精氨酸 (SR) 蛋白，这些蛋白通过类似于 CDC2 的激酶 (CLKs) 从无膜的核斑移动到核质。这种运动对于 SR 蛋白依赖性的大分子剪接体的组装至关重要。尽管 CLK1 通过磷酸化原型 SR 蛋白 SRSF1 中的丝氨酸-脯氨酸二肽促进这种运输，但一种称为 SR 蛋白激酶 1 (SRPK1) 的不相关酶也具有相同的功能，但不能有效地修饰 SRSF1 中的这些二肽。我们现在表明，SRPK1 将 SRSF1 从斑移动到核质的能力依赖于活性 CLK1。斑点扩散是通过形成 SRPK1-CLK1 复合物来促进的，该复合物促进 SRSF1 与 CLK1 的解离，并增强该 SR 蛋白中几个丝氨酸-脯氨酸二肽的磷酸化。两种激酶的下调都会阻止 EGF 刺激的核 SRSF1 的动员。这些发现建立了一条信号通路，通过相关的 CLK 家族激酶将 SRPKs 与 SR 蛋白激活联系起来。
