Regulation of Cytokinesis in Fission yeast.

描述（由申请人提供）：该项目的长期目标是了解Ndr激酶途径是如何被调节的，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。细胞骨架的重大重排是间期和有丝分裂以及未分化到分化状态之间的过渡所必需的。细胞骨架重排调节不当会产生深远的影响，包括基因组不稳定、干细胞分化缺陷、癌症和转移。真核细胞具有两条保守的Ndr激酶通路，分别在裂变酵母中称为SIN和MOR，在哺乳动物中称为Hippo/Lats和Ndr1/2通路。这两种途径在功能上是不同的：Hippo/Lats和SIN途径在细胞分裂和有丝分裂退出中起作用，而Ndr1/2和MOR途径在细胞极性中起作用。在后生动物中，它们在接触抑制生长、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（Ndr1/2）方面获得了额外的功能。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，但这些途径的靶点却很少。在Specific Aim 1中，我们将确定MOR、Cdk1和SIN之间的信号是如何协调的，以及这种调节在人类细胞中是否保守。我们将在Specific Aim 2中确定新发现的SIN靶点如何在有丝分裂后期调节，以促进细胞分裂、微管组织和纺锤体检查点失活。在Specific Aim 3中，我们将确定Hippo/Lats通路的底物，并测试该通路如何在细胞密度增加时被激活以阻止细胞周期进程的假设。总的来说，这些研究将表明SIN如何通过底物磷酸化和与MOR途径的串扰促进有丝分裂后期事件。我们对Lats2靶点和激活的研究将对肿瘤抑制和组织再生过程具有重要意义。

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.