Regulation and Function of MAPKAP Kinases

描述（由申请人提供）：本提案旨在研究法规和 MAP激酶激活蛋白激酶（MAPKAPKs）的功能， 重要的，扩大，和研究不足的组件在MAP激酶级联。 MAPKs的一个关键作用是控制基因表达。MAPKs和MAPKAPKs 在转录、翻译和稳定化方面进行合作。理解 这种合作对于许多疾病的治疗设计至关重要，因为MAP （丝裂原活化蛋白）激酶（MAPK）级联被激活， 细胞外信号（生长因子、激素、细胞因子）和细胞内信号（生长因子、激素、细胞因子） 信号（细胞压力和检查点）作为互连级联的一部分 酶的激活和抑制控制新陈代谢，基因表达， 和生长发育。这些通路的异常功能 癌症、糖尿病的增殖性并发症和遗传疾病。 有三种主要的MAPK（ERK、JNK和p38 MAPK），但也有许多 同种型。MAP激酶选择特定的目标进行调节，包括成员 被统称为MAPKAPK的一个多样化的群体，它扩展了级联。 MAPKAPK通过它们的C-末端结构域彼此相关， 无论它们具有一个激酶结构域（MNK，MAPKAPK 2）还是两个结构域（RSK， MSK）。 目的一是确定MAP激酶如何结合并调节其特异性MAPKAP 激酶靶点。目的二是研究MAPKAPKs的细胞功能， 调查哺乳动物蛋白质组中由MAPKAPKs诱导的磷酸化。 目的三是设计和应用重组活化的羧基端结构域 （CTDS）以独立地表征其CTD激酶活性 的NTD结构域，并表征核RSK和MSK的提取和 层析 目的四是研究其活化、酶学性质和功能 MAPKAP激酶样酶（Rcklp，Rck 2 p）在酵母，一种模式真核生物，使用 生物化学和遗传学方法相结合。

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.