The role of the NIMA kinase in mitotic regulation

描述（由申请人提供）：有丝分裂调控对所有真核生物至关重要，并且具有医学意义，因为有丝分裂缺陷可导致非整倍体和癌症。有丝分裂是由保守的蛋白激酶的复杂的相互作用，但有一个有限的了解有关的激酶底物和其磷酸化的机制后果。例如，有丝分裂激酶如何在开放有丝分裂期间调节核孔复合体（NPC）的逐步拆卸和重新组装是未知的。我的实验室已经表明，在模式丝状真菌构巢曲霉的封闭有丝分裂过程中，NPC部分分解，至少有12个NPC蛋白（Nups）可逆地从核心NPC结构分散。A.因此，nidulans代表了一种独特的和强大的模型遗传系统，其中NPC在有丝分裂期间以显示出与人类有丝分裂NPC调节许多相似性的方式被调节。有趣的是，A。nidulans An-Nup 2专门重新定位于有丝分裂染色体，表明该Nup具有新的有丝分裂作用。该提案旨在：i）详细定义有丝分裂期间NPC组成的可逆变化，ii）表征NPC结构在分解和组装时如何变化，并将其与NPC组成和功能相关联，iii）建立有丝分裂特异性磷酸化如何调节NPC的结构和功能，和iv）确定An-Nup 2在染色质上的定位如何帮助协调NPC分解/重组与有丝分裂进程。这些研究将有助于确定NPC在有丝分裂过程中如何受到激酶的调节，以及Nups的有丝分裂调节如何与有丝分裂进程相结合。

DESCRIPTION (provided by applicant): Mitotic regulation is fundamentally important to all eukaryotic life and has medical significance as mitotic defects can lead to aneuploidy and cancer. Mitosis is regulated by a complex interplay of conserved protein kinases but there is a limited understanding of the pertinent kinase substrates and the mechanistic consequences of their phosphorylation. For example, it is unknown how mitotic kinases regulate the stepwise disassembly and reassembly of the nuclear pore complex (NPC) during open mitosis. My laboratory has shown that during the closed mitosis of the model filamentous fungus Aspergillus nidulans, the NPC is partially disassembled with at least 12 NPC proteins (Nups) reversibly dispersing from a core NPC structure. A. nidulans therefore represents a unique and powerful model genetic system in which the NPC is regulated during mitosis in a manner displaying many similarities to human mitotic NPC regulation. Interestingly, A. nidulans An-Nup2 exclusively re-locates to mitotic chromosomes, suggesting a novel mitotic role for this Nup. This proposal aims to: i) Define in detail the reversible changes in the composition of the NPC during mitosis, ii) Characterize how NPC architecture changes when it is disassembled and assembled and relate this to NPC composition and function, iii) Establish how mitotic specific phosphorylation regulates the structure and function of the NPC, and iv) Determine how the localization of An-Nup2 to chromatin helps coordinate NPC disassembly/reassembly with mitotic progression. These studies will help define how the NPC is regulated by kinases during mitosis and how the mitotic regulation of Nups is integrated with mitotic progression.