A Model Signaling Mucin in Yeast

酵母中粘蛋白信号传导模型

基本信息

批准号：
7458679
负责人：
PAUL James CULLEN
金额：
$ 7.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458679
关键词：
Adherence Adhesions Adhesives Animal Model Area Aspartic Endopeptidases Biological Models Cancer Detection Candida albicans Cell Adhesion Cell Adhesion Molecules Cell Surface Proteins Cell physiology Cell surface Cell-Cell Adhesion Cells Class Cleaved cell Cues Disease Resistance Endopeptidases Epithelial Event Family GTP-Binding Proteins Genetic Genetic Models Genomics Glycoproteins Goals Head Health Histocompatibility Testing Homeostasis Human Immune system Lubrication MAP Kinase Activation Pathway MAP Kinase Gene Malignant Neoplasms Mammalian Cell Measures Membrane Glycoproteins Microbe Microbial Biofilms Mitogen-Activated Protein Kinases Modeling Molecular Mouth Carcinoma Mucins Neoplasm Metastasis Oral Oral cavity Orthologous Gene Pathogenesis Pathway interactions Peptide Hydrolases Personal Satisfaction Play Process Production Property Protein Family Proteins Receptor Activation Regulation Resistance Role Saccharomycetales Series Signal Pathway Signal Transduction Signaling Molecule Site System Testing Tissues Tooth Demineralization Yeasts cancer therapy insight member microbial mucin receptor oral tissue pathogen prevent protein function receptor tumor

项目摘要

DESCRIPTION (provided by applicant): Mucin glycoproteins comprise a family of cellular adhesions that provide a layer of protection to oral epithelial tissues. Mucin proteins are secreted from the cell where they function in the oral cavity by creating a layer of resistance to microbes, by preventing the demineralization of teeth, and by promoting general lubrication. Mucins are also transcriptionally up-regulated in oral carcinomas (as well as other tumors), which become enriched for mucin production, making mucins ideal molecules for cancer detection and immunological cancer therapies. A recent series of advances demonstrates that mucins can function as signal transduction molecules that activate G-protein and MAP kinase dependent signaling pathways. This new aspect of mucin function is relatively uncharacterized. In this proposal we employ a genetically tractable model organism to understand mucin function and regulation. Specifically, we discovered a mucin receptor in the versatile model organism budding yeast. This mucin, called Msb2, is required for yeast cell-to-cell contact and for biofilm formation. In addition, Msb2 operates at the head of a Cdc42-dependent MAPK pathway. That is, Msb2 is a signaling mucin. We have also found that Msb2, like its mammalian mucin counterparts, is secreted from the cell, and we have identified a family of aspartyl proteases, called yapsins, that are required for liberation of Msb2 from the cell surface. As the proteases required for mucin processing in mammalian cells have yet to be identified, this finding is of broad significance and may be a general feature of mammalian mucins. In this proposal, we seek to understand at a detailed molecular level, the signaling and adhesion functions of this model mucin. In the first aim of this proposal, we propose to dissect the signaling and secretion properties of Msb2. We will confirm that yapsins cleave Msb2, and we will determine if the cleavage event is the cue that triggers receptor activation. In the second aim of this proposal we will purify the secreted form of Msb2 and determine its role in cell adherence and biofilm formation. Our objective is to fully characterize a fungal mucin using a model genetic system. As part of our long-term goals, we will extend our findings to mucin regulation in other systems. Mucins are an important class of adhesion molecules in oral tissues that have recently been shown to function as signaling molecules. Their ability to promote microbial resistance in oral tissues, and their prominence in metastasizing cancers makes these extremely relevant molecules from the perspective of human health. We use a model genetic system - budding yeast - to investigate mucin function in MAP kinase pathway activation, cell adherence, and biofilm formation.

描述（由申请人提供）：粘蛋白糖蛋白包括一个细胞粘连家族，可为口腔上皮组织提供保护。粘蛋白蛋白是通过在口腔中发挥作用的细胞，通过对微生物的抗性，防止牙齿的脱矿化和促进一般润滑来分泌。在口服癌（以及其他肿瘤）中，粘蛋白也被转录上调，这些癌富含粘蛋白的产生，从而使粘蛋白理想的分子用于癌症检测和免疫癌症疗法。最近的一系列进步表明，粘蛋白可以用作激活G蛋白和MAP激酶依赖信号通路的信号转导分子。粘蛋白功能的新方面相对未表征。在此提案中，我们采用了可遗传处理的模型生物来了解粘蛋白功能和调节。具体而言，我们在多功能模型生物萌芽的酵母中发现了粘蛋白受体。该粘蛋白称为MSB2，是酵母细胞与细胞接触和生物膜形成所必需的。此外，MSB2在CDC42依赖性MAPK途径的头部运行。也就是说，MSB2是一种信号粘蛋白。我们还发现，MSB2与其哺乳动物粘蛋白对应物一样，是从细胞中分泌的，我们已经确定了一种称为Yapsins的Aspartyl蛋白酶家族，这些家族是从细胞表面释放MSB2所必需的。由于尚未确定哺乳动物细胞中粘蛋白加工所需的蛋白酶，因此该发现具有广泛的意义，可能是哺乳动物粘蛋白的一般特征。在此提案中，我们试图在详细的分子水平上理解该模型粘蛋白的信号传导和粘附功能。在该提案的第一个目的中，我们建议剖析MSB2的信号传导和分泌特性。我们将确认Yapsins裂解MSB2，我们将确定裂解事件是否是触发受体激活的提示。在该提案的第二个目的中，我们将净化MSB2的分泌形式，并确定其在细胞依从性和生物膜形成中的作用。我们的目标是使用模型遗传系统充分表征真菌粘蛋白。作为我们长期目标的一部分，我们将把发现扩展到其他系统中的粘蛋白调节。粘蛋白是口腔组织中一类重要的粘附分子，这些分子最近被证明是信号分子的作用。它们在口腔组织中促进微生物抗性的能力及其在转移癌中的突出性使这些非常相关的分子从人类健康的角度。我们使用模型遗传系统 - 芽酵母 - 研究MAP激酶途径激活，细胞粘附和生物膜形成中的粘蛋白功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Shedding of the mucin-like flocculin Flo11p reveals a new aspect of fungal adhesion regulation.

DOI：
10.1016/j.cub.2010.06.033
发表时间：
2010-08-10
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Karunanithi, Sheelarani;Vadaie, Nadia;Chavel, Colin A.;Birkaya, Barbara;Joshi, Jyoti;Grell, Laura;Cullen, Paul J.
通讯作者：
Cullen, Paul J.

Multiple signals converge on a differentiation MAPK pathway.