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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：
10224750
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224750
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会促进癌症和神经系统疾病等疾病的发生紊乱细胞极性丧失和组织结构破坏是癌症中常见的组织学特征，在组织结构的改变中起重要作用。虽然取得了实质性进展，协调细胞形态和细胞生长的分子机制仍然知之甚少。很长的- 我们实验室的长期目标是了解控制细胞形状出现的细胞功能，特别是协调细胞极性和细胞生长的信号网络。保守的NDR激酶在细胞形态和细胞增殖的控制中起关键作用，从酵母到哺乳动物的多种生物。目前，人们对这一问题的认识非常有限。这种保守激酶及其靶点的细胞功能。我们之前发现裂变酵母 NDR激酶Orb 6在空间上调节Cdc 42 GT3的活性，Cdc 42 GT3是一种关键的形态控制因子。最近，我们已经表明Orb 6激酶也负调节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，我们已经确定了新的 Orb 6激酶的靶点，并发现了Orb 6激酶在促进细胞适应中的新作用，静止期的按时间顺序的寿命。该项目的目标是确定机制， NDR激酶在空间上调节细胞形状，促进细胞生长并在酵母和酵母中培养细胞弹性。人体细胞在《特异性目标1》中，我们将定义NDR激酶如何磷酸化关键底物，形状出现。在特异性Aim 2中，我们将确定NDR激酶如何调节特异性mRNA结合控制极化细胞生长的蛋白质。在特异性目标3中，我们将确定NDR激酶在使替代生理状态，从活跃的细胞生长到细胞静止，以促进细胞恢复力。