Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones
Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones
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DOI：
10.1101/gad.1752109
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发表时间：
2009-02-15
影响因子：
10.5
通讯作者：
Fu, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Zhong, Xiang-Yang;Ding, Jian-Hua;Fu, Xiang-Dong
磷酸化是SR家族剪接因子/调节因子在组成性和受调节的pre-mRNA剪接中发挥作用所必需的；然而，已知SR蛋白的低磷酸化和高磷酸化都会抑制剪接，这表明SR蛋白的磷酸化在细胞中必须受到严格调节。然而，SR蛋白磷酸化在发育过程中或对特定信号事件的反应中是如何调节的，我们知之甚少。在此，我们报道了SRPK1是一种普遍表达的SR蛋白特异性激酶，它直接结合于哺乳动物细胞中的伴侣蛋白Hsp40/DNAjc8和Aha1，从而介导该激酶与主要分子伴侣蛋白Hsp70和Hsp90的动态相互作用。抑制Hsp90 atp酶活性诱导SRPK1从伴侣复合物中分离，这也可以由应激信号（渗透休克）触发，导致激酶从细胞质向细胞核的易位，SR蛋白的差异磷酸化和剪接位点选择的改变。这些发现将SRPK与分子伴侣系统联系起来，该系统涉及许多信号转导途径，并为SR蛋白磷酸化和选择性剪接的复杂调控提供了机制见解，以响应发育线索和细胞信号。
Phosphorylation is essential for the SR family of splicing factors/regulators to function in constitutive and regulated pre-mRNA splicing; yet both hypo- and hyperphosphorylation of SR proteins are known to inhibit splicing, indicating that SR protein phosphorylation must be tightly regulated in the cell. However, little is known how SR protein phosphorylation might be regulated during development or in response to specific signaling events. Here, we report that SRPK1, a ubiquitously expressed SR protein-specific kinase, directly binds to the cochaperones Hsp40/DNAjc8 and Aha1, which mediate dynamic interactions of the kinase with the major molecular chaperones Hsp70 and Hsp90 in mammalian cells. Inhibition of the Hsp90 ATPase activity induces dissociation of SRPK1 from the chaperone complexes, which can also be triggered by a stress signal ( osmotic shock), resulting in translocation of the kinase from the cytoplasm to the nucleus, differential phosphorylation of SR proteins, and alteration of splice site selection. These findings connect the SRPK to the molecular chaperone system that has been implicated in numerous signal transduction pathways and provide mechanistic insights into complex regulation of SR protein phosphorylation and alternative splicing in response to developmental cues and cellular signaling.