Signaling mechanisms in cell polarity in yeast

酵母细胞极性的信号机制

• 批准号: 7932353
• 负责人: Erfei Bi
• 金额: $ 10.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932353
• 关键词: Actins; Address; Affect; Biology; Cell Cycle; Cell Polarity; Cell Shape; Cell division; Cell membrane; Cell physiology; Cell surface; Cells; Cellular Stress; Cellular biology; Clinical Sciences; Complex; Cytokinesis; Cytoskeleton; Daughter; Defect; Dendritic Spines; Development; Development Polarity; Diffusion; Endocytosis; Epithelium; Eukaryota; Eukaryotic Cell; Event; Exocytosis; Family; Filament; GTP Binding; GTPase-Activating Proteins; Gatekeeping; Generations; Genetic; Growth; High temperature of physical object; Homologous Gene; Human Genome; Maintenance; Malignant Neoplasms; Mammals; Mediating; Microtubules; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mothers; Myosin Type II; Neck; Neurons; Nutrient; Pathway interactions; Phenotype; Play; Process; Proteins; Regulation; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Scaffolding Protein; Signal Transduction; Site; System; Testing; Time; Yeasts; base; cell growth; cell motility; daughter cell; human disease; in vivo; inhibitor/antagonist; mutant; neurotransmission; novel; polymerization; prevent; protein distribution; protein function; public health relevance; rab GTP-Binding Proteins; research study; rho GTP-Binding Proteins; rho GTPase-activating protein; role model; scaffold

DESCRIPTION (provided by applicant): Cell polarity is essential for development and differentiation, and it plays vital roles in fundamental processes such as cell migration, nutrient transport across epithelia, and neuronal transmission. Defects in cell polarity are often associated with serious human diseases such as cancer. Our long-term objective is to use the genetically tractable eukaryote Saccharomyces cerevisiae to elucidate the principles of cell polarization. In this proposal, we will address two important questions regarding the central role of Cdc42p, an evolutionarily conserved small GTPase, in polarity development. In Aim1, we will determine how Cdc42p activity is spatiotemporally regulated by its GAPs, Rga1p and Bem2p, in the formation of a single polarization domain, a common issue among all polarization systems. There are four GAPs (Rga1p, Rga2, Bem3p, and Bem2p) known to act on Cdc42p. Previously, we and others have shown that three GAPs (Rga1p, Rga2, and Bem3p) share a role in septin ring assembly at the beginning of the cell cycle. Recently, we discovered that Rga1p is uniquely required for preventing polarization within old cell division sites in post-cytokinesis cells. In this proposal, we will test our novel idea that Rga1p and Bem2p function redundantly at the bud neck as "gatekeepers" to restrict active Cdc42p and Rho1p to a single polarization domain, the bud cortex. To date, our studies have indicated that different GAPs can act alone or together to regulate specific cellular processes involving Cdc42p, and have helped establish a paradigm for studying complex regulation of mammalian Rho GTPases (~17 in human genome) by their numerous GAPs (~68 Rho GAPs in human genome). In Aim2, we will propose experiments to test our integrative model for the role of Cdc42p in polarized actin and septin organization, which together determine the overall cell shape and dictate their diverse functions in fundamental processes such as polarized exocytosis and directed cell migration. Our model states that Cdc42p controls polarized actin and septin organization via two genetically separable, but biochemically cross-talking pathways, one involving the evolutionarily conserved "polarisome" that is centered on the formin Bni1p, scaffold protein Spa2p, and the Rab GAPs Msb3p and Msb4p, and the other involving the yeast-specific Cdc42p effectors Gic1p and Gic2p. In this proposal, we will determine how the polarisome pathway affects septin organization via the actin cytoskeleton, how the Gic pathway affects actin organization via the septins, and how these two pathways crosstalk under cellular stresses such as 370C via Spa2p-based interactions. Homologues of Cdc42p are involved in numerous cellular functions such as cell polarity, cell migration, and cell growth control. Deregulation of Cdc42p activity in mammals is associated with serious human diseases, such as cancer. Thus, studying the signaling mechanisms of Cdc42p in yeast will have profound implication in basic biology and clinical sciences. PUBLIC HEALTH RELEVANCE: Cdc42p, an evolutionarily conserved small GTPase, plays essential roles in diverse cellular processes such as cell polarity, cell migration, and cell growth control. Deregulation of Cdc42p activity in mammals is associated with serious human diseases, such as cancer. Thus, studying the signaling mechanisms of Cdc42p in yeast will have profound implication in basic biology and clinical sciences.

描述（由申请人提供）：细胞极性对于发育和分化至关重要，并且在基本过程中起着至关重要的作用，例如细胞迁移，遍布上皮的营养运输和神经元传播。细胞极性缺陷通常与严重的人类疾病（如癌症）有关。我们的长期目标是使用酿酒酵母的遗传学可核核糖糖果糖果糖阐明细胞极化的原理。在此提案中，我们将解决有关Cdc42p（进化保守的小GTPase）在极性发展中的核心作用的两个重要问题。在AIM1中，我们将确定CDC42P活性如何由其差距，RGA1P和BEM2P的空间调节，在形成单个极化域中，这是所有极化系统中常见的问题。已知在Cdc42p上作用的四个差距（RGA1P，RGA2，BEM3P和BEM2P）。以前，我们和其他人已经表明，在细胞周期开始时，三个差距（RGA1P，RGA2和BEM3P）在Septin环组件中具有作用。最近，我们发现RGA1p是防止旧细胞分裂位点在循环细胞中的极化所必需的。在此提案中，我们将测试我们的新颖想法，即RGA1P和BEM2P在芽脖子上以“守门人”的形式冗余地发挥作用，以将主动的Cdc42p和Rho1p限制为单个极化域，即Bud Cortex。迄今为止，我们的研究表明，不同的间隙可以单独起作用或共同调节涉及Cdc42p的特定细胞过程，并有助于建立一个范式，以研究哺乳动物Rho GTPase（人类基因组中的〜17）的复杂调节，其大量差距（在人类基因组中约为68个Rho Gaps）。在AIM2中，我们将提出实验，以测试CDC42P在极化肌动蛋白和SEPTIN组织中的作用的整合模型，这些模型共同确定了整体细胞形状，并决定了它们在诸如偏振胞症和定向细胞迁移之类的基本过程中的各种功能。我们的模型指出，CDC42P通过两个具有遗传分离但生物化学上的跨语言途径来控制极化的肌动蛋白和隔膜组织，一种涉及进化保守的“极性组”，该途径以甲型BNI1P，BNI1P，scaffold Protein spa2p以及Rab gaps MSB4P和其他Yeast CDC CDC CDC CDC和其他效果为中心，以及YEAST YEAST-SPECCIC CDCICIC ANDECIC ANDECIC ANDECIC ANDECIC CDCICIC ANDECIC ANDECIC ANDECIC ANDECIC ANDPIC ANDP-SPECIC ANDP-SPECIC ANDECIC ANDP。 GIC2P。在此提案中，我们将通过肌动蛋白细胞骨架，如何通过septins来确定极化途径如何通过肌动蛋白细胞骨架影响SEPTIN组织，GIC途径如何影响肌动蛋白组织，以及这两种途径如何通过基于SPA2P的相互作用在370C（例如370C）下进行串扰。 Cdc42p的同源物参与许多细胞功能，例如细胞极性，细胞迁移和细胞生长控制。哺乳动物中Cdc42p活性的放松调节与严重的人类疾病（例如癌症）有关。因此，研究酵母中Cdc42p的信号传导机制将对基本生物学和临床科学产生深远的影响。 公共卫生相关性：CDC42P是一种进化保守的小GTPase，在各种细胞过程中起着至关重要的作用，例如细胞极性，细胞迁移和细胞生长控制。哺乳动物中Cdc42p活性的放松调节与严重的人类疾病（例如癌症）有关。因此，研究酵母中Cdc42p的信号传导机制将对基本生物学和临床科学产生深远的影响。