Regulation of Cytokinesis in Fission yeast.

描述（由申请人提供）：本项目的长期目标是了解Ndr激酶通路如何调节，并在细胞周期进程、细胞骨架组织、肿瘤抑制和干细胞分化中发挥重要作用。细胞骨架的主要重排需要间期和有丝分裂之间的过渡，以及未分化的分化状态。不能正确调节细胞骨架重排可能产生深远的影响，包括基因组不稳定性，干细胞分化缺陷，癌症和转移。真核细胞具有两个保守的Ndr激酶途径，在裂殖酵母中称为SIN和莫尔（S. pombe）或哺乳动物中的Hippo/Lats和Ndr 1/2途径。这两条途径在功能上是不同的：Hippo/Lats和SIN途径在胞质分裂和有丝分裂退出中起作用，而Ndr 1/2和莫尔途径在细胞极性中起作用。在后生动物中，它们还具有接触抑制生长、肿瘤抑制和干细胞分化（Hippo/Lats）或促进生长、染色体聚集和中心体复制（Ndr 1/2）的额外功能。尽管它们在细胞分裂、细胞极性和发育中起着至关重要的作用，但这些途径的靶点很少。在具体目标1中，我们将确定信号传导如何在莫尔、Cdk 1和SIN之间协调，以及这种调节在人类细胞中是否保守。我们将在具体目标2中确定新发现的SIN靶点如何在有丝分裂晚期调节，以促进胞质分裂，微管组织和纺锤体检查点失活。在特定目标3中，我们将识别Hippo/Lats途径的底物，并测试该途径如何响应细胞密度增加而被激活以阻止细胞周期进展的假设。总之，这些研究将显示SIN如何通过底物磷酸化和与莫尔通路的串扰促进晚期有丝分裂事件。我们对Lats 2靶点和激活的研究将对肿瘤抑制和组织再生过程产生重要影响。 公共卫生相关性：本提案中研究的途径在细胞增殖、癌症和干细胞分化中具有重要功能。这项工作将提供重要的洞察这些途径如何工作，以及他们的活动是如何被调节，这应该导致癌症和组织工程的治疗方法。)

DESCRIPTION (provided by applicant): The long term goals of this project are to understand how Ndr kinase pathways are regulated and carry out their important roles in cell cycle progression, cytoskeletal organization, tumor suppression, and stem cell differentiation. Major rearrangements of the cytoskeleton are required for the transition between interphase and mitosis as well as undifferentiated to differentiated states. Failure to properly regulate cytoskeletal rearrangements can have profound effects including genomic instability, stem cell differentiation defects, cancer, and metastasis. Eukaryotic cells possess two conserved Ndr kinase pathways, called the SIN and MOR in fission yeast (S. pombe) or the Hippo/Lats and Ndr1/2 pathways in mammals. The two pathways are functionally distinct: the Hippo/Lats and SIN pathways play roles in cytokinesis and mitotic exit whereas the Ndr1/2 and MOR pathways function in cell polarity. In metazoans they have acquired additional functions in contact inhibition of growth, tumor suppression, and stem cell differentiation (Hippo/Lats), or growth promotion, chromosome congression and centrosome duplication (Ndr1/2). Despite their crucial functions in cell division, cell polarity, and development, few targets of these pathways are known. In Specific Aim 1, we will determine how signaling is coordinated between the MOR, Cdk1, and the SIN and whether this regulation is conserved in human cells. We will determine in Specific Aim 2 how newly identified targets of the SIN are regulated in late mitosis to promote cytokinesis, microtubule organization, and spindle checkpoint inactivation. In Specific Aim 3, we will identify substrates of the Hippo/Lats pathway and test hypotheses for how the pathway is activated in response to increased cell density to stop cell cycle progression. Overall these studies will show how the SIN promotes late mitotic events through substrate phosphorylation and crosstalk with the MOR pathway. Our studies on Lats2 targets and activation will have important implications for the processes of tumor suppression and tissue regeneration. PUBLIC HEALTH RELEVANCE: The pathways studied in this proposal have important functions in cell proliferation, cancer, and stem cell differentiation. This work will provide important insight into how these pathways work and how their activities are be regulated, which should lead to therapeutic approaches for cancer and tissue engineering. )