Regulation and Function of MAPKAP Kinases

描述(申请人提供)：本提案是为了研究法规和 MAPKAPKs的功能，它们是 MAP激酶级联中重要的、不断扩展的和未被充分研究的组成部分。 MAPKs的一个关键作用是控制基因的表达。MAPK和MAPKAPK 在转录、翻译和稳定方面进行协作。理解 这种合作对设计许多疾病的治疗方法至关重要，因为MAP (丝裂原活化蛋白)激酶(MAPK)级联通路由 细胞外信号(生长因子、激素、细胞因子)和细胞内信号 作为互联级联的一部分的信号(细胞压力和检查点) 酶的激活和抑制控制新陈代谢，基因表达， 以及成长和发展。这些通路的异常功能参与了 癌症、糖尿病的增殖性并发症和遗传性疾病。 有三种主要的MAPK(ERK、JNK和p38MAPK)，但有许多 异构体。Map Kinks选择要监管的特定目标，包括成员 一种不同的群体，统称为MAPKAPK，它延伸了级联。 MAPKAPK通过其C-末端结构域相互关联，独立于 它们是否具有一个激动域(MNKs，MAPKAPK2)或两个结构域(RSKs， MSK)。 目的一是确定MAPKAP如何结合和调节其特定的MAPKAP 激酶靶标。目的二研究MAPKAPKs的细胞功能。 研究哺乳动物蛋白质组中MAPKAPKs诱导的磷酸化。 目的三是设计和使用重组激活的COOH-末端结构域 RSKs和MSKs的CTD，以独立地表征其CTD激酶活性 并通过提取和鉴定核RSKs和MSKs 层析法。 目的四是表征酶的激活、酶性质和功能 在模式真核生物酵母中对MAPKAP类激活酶(Rck lp，Rck 2p)的研究 生物化学和遗传学相结合的方法。

DESCRIPTION (provided by applicant): This proposal is to study regulation and function of MAP kinase-activated protein kin ses (MAPKAPKs), which are important, expanding, and understudied components in the MAP kinase cascades. One key role of MAPKs is to control gene expression. MAPKs and MAPKAPKs collaborate in transcription, translation, and stabilization. Understanding this collaboration is vital to design of therapies in many diseases because MAP (mitogen-activated protein) kinase (MAPK) cascades are activated by extracellular signals (growth factors, hormones, cytokines) and intracellular signals (cellular stresses and checkpoints) as part of interconnected cascades of enzyme activations and inhibitions controlling metabolism, gene expression, and growth and development. Abnormal functions of the pathways is involved in cancer, proliferative complications of diabetes, and genetic disorders. There are three principal MAPKs (ERK, JNK, and p38 MAPK) but there are many isoforms. MAP kinases select specific targets for regulation, including members of a diverse group called collectively MAPKAPKs which extend the cascade. MAPKAPKs are related to each other by their C-terminal domains independent of whether they have one kinase domain (MNKs, MAPKAPK2) or two domains (RSKs, MSKs). Aim one is determine how MAP kinases bind and regulate their specific MAPKAP kinase targets. Aim two is to study the cellular functions of MAPKAPKs by surveying the mammalian proteome for phosphorylations inducible by MAPKAPKs. Aim three is to design and use recombinant activated COOH-terminal domains (CTDS) of RSKs and MSKs to characterize their CTD kinase activity independently of the NTD domain, and to characterize nuclear RSKs and MSKs by extraction and chromatography. Aim four is to characterize the activation, enzymatic properties, and functions of MAPKAP kinase-like enzymes (Rcklp, Rck2p) in yeast, a model eukaryote, using combined biochemical and genetic approaches.