Control of cell morphogenesis and cell growth by conserved NDR kinase Orb6

保守的 NDR 激酶 Orb6 对细胞形态发生和细胞生长的控制

基本信息

批准号：
10455097
负责人：
FULVIA VERDE
金额：
$ 30.7万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455097
关键词：
Antibodies Architecture Area Binding Proteins Biochemical Biological Assay Brain Cardiac Cell Aging Cell Differentiation process Cell Polarity Cell Proliferation Cell Shape Cell Survival Cell physiology Cells Cellular Morphology Chronology Cytoplasm Defect Development Disease Down-Regulation Enzymes Eukaryota Exploratory Behavior Fission Yeast Fostering Gastric lymphoma Genetic Genetic Models Genomics Goals Growth Guanosine Triphosphate Phosphohydrolases Histologic Homeostasis Human KRP protein Laboratories Link Longevity Malignant Neoplasms Mammals Messenger RNA Microscopic Molecular Morphogenesis Morphology Neurodegenerative Disorders Neurons Nuclear Nutritional Nutritive Value Onset of illness Organism Pathway interactions Pattern Phosphorylation Phosphotransferases Physical condensation Physiological Play Proteomics Public Health Research Ribonucleoproteins Role Scientist Signal Pathway Signal Transduction Starvation Stomach Neoplasms Stress T-Cell Lymphoma Testing Tissues Translational Repression Yeasts biochemical model biophysical properties cancer cell carcinogenesis cell growth cellular targeting detection of nutrient diagnostic biomarker genetic analysis improved insight mRNA Transcript Degradation malignant stomach neoplasm mathematical model nervous system disorder novel novel diagnostics particle polarized cell resilience screening self organization therapeutic target

项目摘要

Defects in cell morphogenesis promote the onset of diseases such as cancer and neurological disorders. Loss of cell polarity and disruption of tissue architecture is a common histological feature in cancer, playing an important role in the alteration of tissue organization. Although substantial progress has been made, the molecular mechanisms coordinating cell morphology and cell growth are still poorly understood. The long- term goal of our laboratory is to understand the cellular functions that govern cell shape emergence, and in particular the signaling networks that coordinate cell polarity with cell growth. The conserved NDR kinase plays a key role in the control of cell morphology and cell proliferation in several organisms ranging from yeast to mammals. Currently, there is a very limited understanding of the cellular functions of this conserved kinase and of its targets. We have previously discovered that fission yeast NDR kinase Orb6 spatially regulates the activity of Cdc42 GTPase, a key morphology control factor. Recently, we have shown that Orb6 kinase also negatively regulates mRNA degradation and translational repression, promoting polarized cell growth. Using genomic-scale and proteomic approaches we have identified novel targets of Orb6 kinase, and discovered a novel role for Orb6 kinase in promoting cell adaptation and chronological lifespan during quiescence. The objective of this project is to define the mechanisms whereby NDR kinase spatially regulates cell shape, promotes cell growth and foster cell resilience in both yeast and human cells. In Specific Aim1, we will define how NDR kinase phosphorylates key substrates to enable cell shape emergence. In Specific Aim2, we will determine how NDR kinase regulates specific mRNA binding proteins to control polarized cell growth. In Specific Aim3, we will establish the role of NDR kinase in enabling alternative physiological states, from active cell growth to cell quiescence, to promote cell resilience.

细胞形态发生的缺陷促进癌症和神经系统疾病的发作疾病。细胞极性的丧失和组织结构的破坏是癌症中常见的组织学特征，在组织组织的改变中发挥重要作用。尽管已经取得了很大的进步，但协调细胞形态和细胞生长的分子机制仍然鲜为人知。长期我们实验室的术语目标是了解控制细胞形状出现的细胞功能，并在尤其是将细胞极性与细胞生长进行协调的信号网络。保守的NDR激酶在控制细胞形态和细胞增殖中起关键作用从酵母到哺乳动物的几种生物。目前，对该保守激酶及其靶标的细胞功能。我们以前已经发现裂变酵母 NDR激酶ORB6在空间上调节Cdc42 GTPase的活性，Cdc42 GTPase是一个关键的形态控制因子。最近，我们已经表明，ORB6激酶还负调节mRNA降解和翻译抑制，促进极化细胞生长。使用基因组规模和蛋白质组学方法，我们已经确定了新颖的 ORB6激酶的靶标，发现ORB6激酶在促进细胞适应和静止期间的年代寿命。该项目的目的是定义机制 NDR激酶在空间调节细胞形状，促进细胞生长并促进酵母和人类细胞。在特定的AIM1中，我们将定义NDR激酶如何磷酸化关键底物以启用细胞形状出现。在特定的AIM2中，我们将确定NDR激酶如何调节特定的mRNA结合蛋白质以控制极化细胞的生长。在特定的AIM3中，我们将确定NDR激酶在启用中的作用从活性细胞生长到细胞静止，替代生理状态，以促进细胞弹性。