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首页> 外文学位 >Vimentin is recruited to the cell surface by beta3 integrin and plectin: Role in mediating adhesion strength and cellular motility.
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Vimentin is recruited to the cell surface by beta3 integrin and plectin: Role in mediating adhesion strength and cellular motility.

机译：波形蛋白被beta3整合素和Plectin募集到细胞表面：在介导粘附强度和细胞运动性中起作用。

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摘要

New blood vessels can be formed by one of two related but distinct mechanisms -- vasculogenesis or angiogenesis. Vasculogenesis is defined as the development of blood vessels from angioblast precursor cells, whereas angiogenesis is the formation of new blood vessels from existing vasculature [1]. The formation of new blood vessels facilitates the physiological processes of embryonic development, female reproduction and wound healing [2]. Pathological angiogenesis is known to play a role in solid tumor formation, metastasis, diabetic retinopathy, macular degeneration, psoriasis and in inflammation-related diseases such as rheumatoid arthritis and ulcerative colitis [2]. Much attention has been paid to deregulated angiogenesis in cancer as the expansion of solid tumors beyond a minimal size is critically dependent on the formation of new blood vessels to supply oxygen, nutrients and growth factors [2]. Indeed, a high degree of vascularization in certain tumors indicates a poor clinical prognosis and increased risk of metastasis [3]. Angiogenesis involves endothelial cell (EC) migration from preexisting blood vessels, formation of adhesive sites between migrating cells and the extracellular matrix (ECM), and assembly of ECs into vessels [4]. Focal adhesion (FA) proteins play a role in each of these processes [5]. A focal adhesion is defined as a site of close interaction between the cell and its substrate [6]. In the case of ECs, this is the site where the cells are in close contact with the basement membrane of the blood vessel [7].;FAs are enriched in matrix receptors of the integrin family that connect the ECM with the cytoskeleton of an EC. Integrins are a family of heterodimeric transmembrane proteins comprising at least 18 alpha and 8 beta subunits, which form 24 known alphabeta-heterodimers depending on cell type and cellular function. Ligand binding to the extracellular integrin domain induces conformational changes and integrin clustering for activation of signaling cascades and recruitment of multiprotein complexes to FAs [8, 9]. At least seven members of the integrin family play important roles in EC biology: alphavbeta3, alphavbeta5, alphavbeta1, alpha5beta1, alpha3beta1, alpha2beta1, and alpha1beta1 [10]. In the developing vasculature and during angiogenesis, alphavbeta3 integrin is a major receptor expressed by ECs at FAs [4]. Historically, the largest amount of data pointed to alphavbeta3 integrin, a receptor for both fibronectin and vitronectin, and alphavbeta5, a vitronectin receptor, as major players in blood vessel formation. Indeed, blockade of alphavbeta3 or alphavbeta5 integrins with antagonists disrupts tumor and experimental angiogenesis [11-13]. However, genetic ablation of alphav, beta3, or beta3/beta5 integrin subunits in mice has relatively no effect on angiogenesis [14, 15]. In fact, mice lacking beta3 or beta3/beta5 integrin subunits show enhanced tumor growth and angiogenesis [14]. While the importance of alphavbeta3 in the vasculature is recognized, its exact role remains controversial and further research is required to determine its functions.;My project is designed to determine whether alphavbeta3 integrin mediates vimentin IF-FA association (Chapter 3) and how these interactions regulate not only the functions of alphavbeta3 integrin but also the adhesive and migratory behavior of ECs (Chapter 5), since the adhesion and migration of ECs plays important roles in both normal functions of the vasculature as well as during times of vascular remodeling. I have also investigated the role of plectin in linking the IF cytoskeleton to beta3 integrin and how microtubule motor proteins play a role in the recruitment of 6 vimentin IF to FAs in ECs (Chapter 4). Finally, I have done some studies on the effect of specific ECM ligands on integrin cross-talk, and how this cross-talk affects integrin recruitment to FAs and vimentin IF interaction with these FAs (Chapter 6).;In summary, my research demonstrates the importance of IF association with beta3 integrin in ECs, the mechanisms by which this association is made, and finally, the consequences of this association to EC function. Specifically, I have shown that IF recruitment to FAs in ECs requires beta3 integrin and plectin, and is mediated by microtubule motors. In CHO cells, which lack beta3 integrin but contain vimentin, IF are localized around the nucleus whereas in CHO cells expressing beta3 integrin (CHOwtbeta3), vimentin IFs extend to FAs at the cell periphery. This recruitment is regulated by tyrosine residues in the beta3 integrin tail. Moreover, CHOwtbeta3 cells exhibit significantly greater adhesive strength and motility than CHO or CHO cells expressing mutated beta3 integrin proteins. These differences require an intact vimentin network. Therefore, vimentin IF recruitment to the cell surface is tightly regulated and modulates the strength of adhesion of cells to their substrate as well as their ability to migrate over the substrate. (Abstract shortened by UMI.)
机译：新血管可以通过以下两种相关但截然不同的机制之一形成：血管生成或血管生成。血管生成被定义为由成血管细胞前体细胞形成的血管，而血管生成则是由现有脉管系统形成的新血管[1]。新血管的形成促进了胚胎发育，雌性生殖和伤口愈合的生理过程[2]。众所周知，病理性血管生成在实体瘤形成，转移，糖尿病性视网膜病，黄斑变性，牛皮癣以及与炎症相关的疾病（如类风湿性关节炎和溃疡性结肠炎）中起作用[2]。实体瘤的扩展超出最小尺寸至关重要，这主要取决于新血管的形成以提供氧气，养分和生长因子[2]，从而使癌症中血管生成的失调引起了人们的极大关注。确实，某些肿瘤中高度的血管形成表明临床预后较差，转移的风险增加[3]。血管生成涉及内皮细胞（EC）从既有血管的迁移，迁移细胞与细胞外基质（ECM）之间的粘附位点的形成以及ECs组装入血管[4]。黏着斑（FA）蛋白在这些过程中均起作用[5]。粘着斑定义为细胞与其底物之间紧密相互作用的部位[6]。对于EC，这是细胞与血管基底膜紧密接触的部位[7]。FA富含整合素家族的基质受体，这些受体将ECM与EC的细胞骨架相连。整联蛋白是包含至少18个α和8个β亚基的异二聚跨膜蛋白家族，其取决于细胞类型和细胞功能而形成24个已知的字母-异二聚体。配体与细胞外整合素结构域的结合诱导构象变化和整合素簇集，从而激活信号级联反应并将多蛋白复合物募集到FA中[8，9]。整合素家族的至少七个成员在EC生物学中起重要作用：alphavbeta3，alphavbeta5，alphavbeta1，alpha5beta1，alpha3beta1，alpha2beta1和alpha1beta1 [10]。在发育中的脉管系统中和血管生成过程中，αvbeta3整合素是EC在FA上表达的主要受体[4]。从历史上看，最大的数据表明纤连蛋白和玻连蛋白的受体αvbeta3整合素和玻连蛋白受体αvbeta5是血管形成的主要参与者。实际上，用拮抗剂阻断αvbeta3或αvbeta5整合素会破坏肿瘤和实验性血管生成[11-13]。但是，小鼠中αv，β3或β3/β5整合素亚基的遗传消融对血管生成没有影响[14，15]。事实上，缺乏beta3或beta3 / beta5整合素亚基的小鼠显示出增强的肿瘤生长和血管生成[14]。尽管人们认识到alphavbeta3在脉管系统中的重要性，但其确切作用仍存在争议，需要进一步研究以确定其功能。我的项目旨在确定alphavbeta3整合素是否介导波形蛋白IF-FA结合（第3章）以及这些相互作用如何不仅调节αvbeta3整联蛋白的功能，而且调节EC的粘附和迁移行为（第5章），因为EC的粘附和迁移在脉管系统的正常功能以及血管重塑期间均起着重要作用。我还研究了凝集素在将IF细胞骨架与β3整联蛋白连接中的作用，以及微管运动蛋白如何在6种波形蛋白IF向EC的FA募集中发挥作用（第4章）。最后，我对特定ECM配体对整联蛋白串扰的影响进行了一些研究，以及这种串扰如何影响整联蛋白向FA的募集以及波形蛋白IF与这些FA的相互作用（第6章）。总之，我的研究表明IF与beta3整合素在EC中的重要性，建立这种联系的机制，以及最后这种联系对EC功能的后果。具体来说，我已经表明，如果要在EC中将FA募集到IF，则需要beta3整合素和Plectin，并且是由微管马达介导的。在缺少beta3整合素但含有波形蛋白的CHO细胞中，IF位于细胞核周围，而在表达beta3整合蛋白（CHOwtbeta3）的CHO细胞中，波形蛋白IFs延伸至细胞周围的FA。这种募集受到beta3整联蛋白尾巴中酪氨酸残基的调控。此外，与表达突变的β3整联蛋白的CHO或CHO细胞相比，CHOwtbeta3细胞表现出明显更高的粘附强度和运动性。这些差异需要完整的波形蛋白网络。因此波形蛋白IF募集到细胞表面受到严格调节，并调节细胞与其底物的粘附强度以及在底物上迁移的能力。 （摘要由UMI缩短。）

著录项

  • 作者

    Bhattacharya, Ramona.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 227 p.
  • 总页数 227
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:26

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