Regulation of RNA metabolism and cell growth control by SR protein kinases

描述(由申请人提供)： 这个项目的重点是SRPK1和SRPK2，这是哺乳动物细胞中负责SR蛋白和RS结构域剪接因子和调节因子磷酸化的主要激酶。我们证明了这两种剪接激酶都是通过与分子伴侣的相互作用固定在细胞质中的，并且它们可以被诱导移位到细胞核以响应细胞信号。我们最近发现，这些激酶是激活的Akt的直接底物，代表了EGF途径的一个新分支，调节SR蛋白的磷酸化和细胞核内的选择性剪接。有趣的是，这些剪接蛋白还通过一种新的反馈机制调节Akt的功能状态，因此，我们发现SRPK1的缺失足以转化固定化的MEF。基于这些最新发现，我们现在提出三个具体目标：(1)将SRPKs定义为调控剪接的信号转导分子，结合对关键信号转导途径的生化剖析；(2)通过表征上游信号事件诱导的特定分子开关，阐明SRPK介导的信号转导机制；(3)通过研究SRPKs可能调节Akt并与Akt途径中的其他关键调控因子协同决定细胞命运和促进肿瘤发生的假设，确定SRPKs在肿瘤发生中的功能和调节作用。这些拟议的研究有望对调控剪接、信号转导和癌症生物学产生广泛的影响。 公共卫生相关性： 项目简介这个项目研究了细胞生长信号是如何通过SR蛋白特有的一系列激酶来调节细胞核中的选择性剪接的。这项研究将为理解剪接蛋白激酶的致癌特性奠定基础，从而可能为人类癌症的治疗提供新的策略。

DESCRIPTION (provided by applicant): This project focuses on SRPK1 and SRPK2, major kinases responsible for the phosphorylation of SR proteins and RS domain-containing splicing factors and regulators in mammalian cells. We demonstrated that both of these splicing kinases are anchored in the cytoplasm through interactions with molecular chaperons and that they can be induced to translocate to the nucleus in response to cellular signaling. We recently discovered that these kinases are direct substrates of activated Akt, representing a new branch of the EGF pathway to regulate SR protein phosphorylation and alternative splicing in the nucleus. Interestingly, these splicing kinases also modulate the functional state of Akt via a novel feedback mechanism, and as a functional consequence, we found that depletion of SRPK1 is sufficient to transform immobilized MEFs. Based on these recent findings, we now propose three specific aims to (1) define SRPKs as signal transducers for regulated splicing using global approaches in combination with biochemical dissection of key signal transduction pathways involved, (2) elucidate the mechanism underlying SRPK-mediated signaling by characterizing specific molecular switches induced by upstream signaling events, and (3) determine the function and regulatory role of SRPKs in tumorigenesis by pursuing the hypotheses that SRPKs may regulate Akt and synergize with other key regulators in the Akt pathway to determine cell fate and promote tumorigenesis. The proposed studies are expected to have broad implications on regulated splicing, signal transduction and cancer biology. PUBLIC HEALTH RELEVANCE: Project Narrative This project addresses how cell growth signals are transduced to regulate alternative splicing in the nucleus via a family of kinases specific for SR proteins. The proposed research will establish the foundation to understand oncogenic properties of the splicing kinasse, which may provide new therapeutic strategies against human cancer.