Investigation of the VEGFR/Integrin cytoplasmic domains interaction.

VEGFR/整合素胞质结构域相互作用的研究。

基本信息

批准号：
7773677
负责人：
OLGA VINOGRADOVA
金额：
$ 22.95万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-12 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7773677
关键词：
Affinity Apoptosis Avidity Binding Biology Blood Blood Cells Blood Vessels Cell Adhesion Cell physiology Cells Clinic Collaborations Communication Complex Cytoplasmic Tail Cytoskeleton Data Development Diabetic Retinopathy Disease Endothelial Cells Endothelium Event Extracellular Domain Extracellular Matrix Family Foundations Generations Growth Factor In Vitro Injury Integrin Binding Integrins Investigation Lead Ligand Binding Link Mediating Modeling Molecular Conformation Mutate Mutation Neoplasm Metastasis Pathogenesis Peptide Signal Sequences Peptides Physiological Play Process Receptor Cross-Talk Regulation Role Series Shapes Signal Transduction Structure System Testing Therapeutic Agents Tissues Tube Tyrosine Phosphorylation Uncertainty Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vitronectin Receptors adhesion receptor angiogenesis base cell motility density design extracellular in vivo migration mutant novel novel therapeutics protein complex protein protein interaction public health relevance receptor response tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The endothelial cells (EC) are often regulated by the signaling from the peptide growth factors and the cellular adhesion receptors. The functional responses include cell adhesion, migration and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. The process of angiogenesis, in turn, plays a crucial role in the pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and tissue remodeling upon injury. During angiogenesis newly produced growth factors, including Vascular Endothelial Growth Factor (VEGF), initiate a series of intricate intracellular events which induce an "inside-out" signal that alters the ligand binding affinity/avidity of the extracellular domains of integrins, the most studied group of heterodimeric transmembrane receptors that connect cells to the extracellular matrix (ECM). Such growth-factor-mediated modulation of integrin ligand binding function, commonly referred to as activation, is most clearly evident in the regulation of blood and vascular cell responses by the ¿ integrin family. Integrin binding triggers conformational changes and clustering of receptors, ultimately leading to the generation of large intracellular protein complexes linked to the cytoskeleton. This physical linkage between extracellular and intracellular compartments allows dynamic regulation of many cellular processes including cell migration, shape change, proliferation and differentiation. Integrin aV¿3, originally identified as the vitronectin receptor, is expressed at variable density on many types of vascular cells, blood cell, tumors and osteocells. It has been demonstrated that one of the key physiological mechanisms of aV¿3 activation on endothelium is via VEGF/VEGF receptor 2 (VEGFR2). EC stimulation by VEGF induces formation of the high affinity state of aV¿3 and, moreover, activated aV¿3 interacts with VEGFR2. A relationship between VEGFR2 and ¿3 integrin appears to be synergistic, since VEGFR2 activation induces ¿3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF induced tyrosine phosphorylation of VEGFR2. It has been also shown that the complex formation between VEGFR2 and aV¿3 is crucial event in regulation of angiogenesis, but the impact and structural requirements for this crosstalk have yet to be determined. In preliminary studies, we have obtained some novel and exciting preliminary data, which suggest that VEGFR2/aV¿3 cytoplasmic tails (CT) are involved in direct interaction. This complex formation between two major EC receptors may underlie a major regulatory mechanism for the regulation of the integrin-dependent functions and for the overall angiogenic response. PUBLIC HEALTH RELEVANCE: This proposal presents the evidence that there is a complex between VEGFR2 and integrin ¿ cytoplasmic tails. We will investigate the exact mechanisms and the role of this interaction: the VEGF-integrin partnership may serve as an important model for fundamental studies of the communication between growth factors and cell adhesion systems. Our data may ultimately lead to a new paradigm for understanding how VEGF and integrin cross talk and regulate the complex cell adhesion events and angiogenic response. Moreover, our structural approach should contribute to the development of new therapeutic agents designed to inhibit integrin (and other receptors) cytoplasmic domain protein-protein interactions.

描述（由适用提供）：内皮细胞（EC）通常受到肽生长因子和细胞粘附受体的信号的调节。功能反应包括细胞粘合剂，迁移和增殖，而这些响应反过来又对更复杂的过程（例如在血管生成过程中形成内皮管网络的形成）至关重要。反过来，血管生成过程在众多疾病的发病机理中起着至关重要的作用，包括但不限于肿瘤生长/转移，糖尿病性视网膜病和损伤后的组织重塑。在血管生成期间，新产生的生长因子（包括血管内皮生长因子（VEGF））启动了一系列复杂的细胞内事件，这些事件诱导了一个“内部”信号，从而改变了整合素的配体结合亲和力/整合素外细胞外域的性交，这是杂膜跨膜受体最多的细胞，这些细胞将其连接到构造的细胞。整联蛋白配体结合功能的这种生长因子介导的调节（通常称为激活）在调节血液和血管细胞反应的调节中最清楚地证明了整合素家族。整合素的结合触发构象变化和接收器的聚类，最终导致与细胞骨架相关的大型细胞内蛋白复合物的产生。细胞外和细胞内室之间的这种物理连接允许动态调节许多细胞过程，包括细胞迁移，形状变化，增殖和分化。整合素Av¿3，最初被鉴定为玻璃连蛋白受体，在多种类型的血管细胞，血细胞，肿瘤和骨细胞上以可变密度表达。已经证明，内皮上AV¿3激活的关键生理机制之一是通过VEGF/VEGF受体2（VEGFR2）。 VEGF刺激的EC诱导了AV¿3的高亲和力状态的形成，而活化的Av？3与VEGFR2相互作用。 VEGFR2和3整联蛋白之间的关系似乎是协同作用的，因为VEGFR2激活诱导»3综合蛋白酪氨酸磷酸化，这反过来对于VEGF诱导VEGFFR2的酪氨酸磷酸化至关重要。还表明，VEGFR2和AV¿3之间的复杂形成是血管生成调节的关键事件，但是该串扰的影响和结构要求尚未确定。在初步研究中，我们获得了一些新颖且令人兴奋的初步数据，这表明VEGFR2/AV¿3细胞质尾巴（CT）参与了直接相互作用。两个主要的EC接收器之间的这种复合形成可能是调节整合素依赖性功能和整体血管生成反应的主要调节机制。公共卫生相关性：该提案提供了一个证据，表明VEGFR2和整合素的细胞质尾巴之间存在复杂性。我们将研究这种相互作用的确切机制和作用：VEGF-整合蛋白的伙伴关系可以作为对生长因子与细胞粘合剂系统之间通信的基本研究的重要模型。我们的数据最终可能导致一个新的范式，以了解VEGF和整合素如何交流并调节复杂的细胞粘合剂事件和血管生成反应。此外，我们的结构方法应有助于开发新的治疗剂，以抑制整联蛋白（和其他受体）细胞质结构域蛋白 - 蛋白质蛋白相互作用。