近日，加州大學(xué)圣地亞哥醫(yī)學(xué)院的研究人員發(fā)現(xiàn)一種新的專門調(diào)控RNA剪接的信號轉(zhuǎn)導(dǎo)通路,，RNA剪接是指從DNA模板鏈轉(zhuǎn)錄出的最初轉(zhuǎn)錄產(chǎn)物中除去內(nèi)含子,，并將外顯子連接起來形成一個連續(xù)的RNA分子的過程。這一發(fā)現(xiàn)發(fā)表在2012年6月27日的Molecular Cell雜志上,，該研究提示新發(fā)現(xiàn)的通路可能是一個新的抗癌藥物作用環(huán)節(jié),。
早期研究證實SRPK1與癌癥和其它人類疾病有關(guān)。例如SRPK1在調(diào)節(jié)血管內(nèi)皮生長因子或血管內(nèi)皮生長因子刺激血液腫瘤血管生長過程中起著關(guān)鍵作用,。在許多癌癥如腎臟、乳腺癌肺癌和胰腺癌等中SRPK1都被證實表達失調(diào),。
Fu和他的同事在這項新的研究中,，發(fā)現(xiàn)了SRPK1存在于一個重要的細胞信號轉(zhuǎn)導(dǎo)通路中，SRPK1在PI3K-Akt通路中發(fā)揮核心作用,。
研究人員認為SRPK是疾病干預(yù)和治療的一大新靶標(biāo),。因為其核心作用，并且易被控制,，抑制其活性可以有效抑制血管形成,。（生物谷：Bioon.com）
doi:10.1016/j.molcel.2012.05.014
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The Akt-SRPK-SR Axis Constitutes a Major Pathway in Transducing EGF Signaling to Regulate Alternative Splicing in the Nucleus
Zhihong Zhou, Jinsong Qiu, Wen Liu, Yu Zhou, Ryan M. Plocinik, Hairi Li, Qidong Hu, Gourisanker Ghosh, Joseph A. Adams, Michael G. Rosenfeld, Xiang-Dong Fu
Pre-mRNA splicing is regulated by developmental and environmental cues, but little is known about how specific signals are transduced in mammalian cells to regulate this critical gene expression step. Here, we report massive reprogramming of alternative splicing in response to EGF signaling. By blocking individual branches in EGF signaling, we found that Akt activation plays a major role, while other branches, such as the JAK/STAT and ERK pathways, make minor contributions to EGF-induced splicing. Activated Akt next branches to SR protein-specific kinases, rather than mTOR, by inducing SRPK autophosphorylation that switches the splicing kinases from Hsp70- to Hsp90-containing complexes. This leads to enhanced SRPK nuclear translocation and SR protein phosphorylation. These findings reveal a major signal transduction pathway for regulated splicing and place SRPKs in a central position in the pathway, consistent with their reputed roles in a large number of human cancers.
