Regulation of a lipid raft trafficking pathway by integrins

整合素对脂筏运输途径的调节

• 批准号: 8044225
• 负责人: Martin A Schwartz
• 金额: $ 39.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044225
• 关键词: Adhesions; Autoimmune Diseases; Caveolae; Cell membrane; Cells; Characteristics; Congenital Abnormality; Cytokine Receptors; Data; Defect; Dependence; Docking; Endosomes; Exocytosis; Extracellular Matrix; Family; Grant; Growth; Growth Factor; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Human; Immune; Integrins; Lead; Link; Malignant Neoplasms; Mediating; Membrane Microdomains; Membrane Protein Traffic; Morphogenesis; Names; Neoplasm Metastasis; Pathway interactions; Process; Proteins; Recycling; Regulation; Role; Signal Pathway; Signal Transduction; System; Tissues; Vesicle; Work; cell behavior; cell growth; cell growth regulation; cell motility; interest; migration; polarized cell; rho; trafficking; transmission process; tumor growth

DESCRIPTION (provided by applicant): Integrin-mediated adhesion controls the transmission of many signals downstream of growth factor and cytokine receptors. These effects modulate cell growth, differentiation and many other functions. Our previous work identified an integrin-regulated membrane trafficking pathway that mediates a number of these effects. Detachment of anchorage- dependent cells from their extracellular matrix triggers internalization of lipid raft components via caveolae. The resultant clearance of these domains from the plasma membrane inhibits growth factor activation of Rho family GTPases, Erk and Akt. Replating cells on extracellular matrix triggers exocytosis of these components to promote cell spreading and restore signaling. During the last grant period, we identified Arf6 as the key determinant of the first step of exocytosis: exit of raft components from the recycling endosomes. We then showed that RalA mediates the next step, docking of exocytic vesicles at the plasma membrane through its interaction with the exocyst. RalA has been implicated as a specific regulator of anchorage-dependence of growth and cancer metastasis in many systems, thus, our data link integrin regulation of membrane trafficking with tumor growth and metastasis. We now propose to investigate the mechanisms by which integrins control the exocytosis pathway and investigate its role in cell motility. Specifically, we will elucidate the mechanism by which integrins regulate RalA during lipid raft exocytosis by identifying the relevant guanine nucleotide exchange factor that mediates integrin activation of RalA and further define the mechanism of activation. We will similarly identify the exchange factors that mediate Arf6 activation and investigate mechanism. Lastly, we will elucidate the role of integrin-regulated lipid raft transport in cell motility, specifically whether there is spatially restricted regulation of lipid raft trafficking via the same pathway and how it contributes to directed cell movement. This work will contribute to our understanding of a pathway that is fundamental to cell behavior as well as crucial in regulating cancer metastasis. PUBLIC HEALTH RELEVANCE: Integrin signaling is one of the basic cellular regulatory mechanisms that governs cell growth, migration, tissue organization and morphogenesis. Defects in these pathways lead to immune deficiencies, autoimmune diseases, birth defects and cancer to name but a few. Integrin signaling mediates anchorage dependence of cell growth, a fundamental mechanism that serves as a safeguard against cancer metastasis. This project aims to elucidate the pathways by which integrins regulate lipid raft vesicular transport and subsequent effects on cell migration and signaling. Our previous work on this pathway has shown that it is regulated by gene products that are highly linked to cancer metastasis. This project therefore has direct relevance for understanding and potentially treating cancer metastasis, as well as important implications for a wide range of morphogenetic and migratory processes in humans.

描述(申请人提供)：整合素介导的黏附控制生长因子和细胞因子受体下游的许多信号的传输。这些效应调节细胞的生长、分化和许多其他功能。我们以前的工作确定了一条整合素调节的膜转运途径，该途径介导了许多这些效应。锚定依赖的细胞从其细胞外基质中分离，触发脂筏成分通过小凹内化。这些结构域从质膜上被清除后，抑制了Rho家族GTPase、Erk和Akt的生长因子激活。在细胞外基质上复制细胞会触发这些成分的胞吐作用，以促进细胞扩散和恢复信号。在上一次资助期间，我们确定Arf6是胞吐作用第一步的关键决定因素：RAFT组分从循环内涵体中退出。然后，我们证明了Rala通过与胞外囊泡的相互作用，介导了下一步，将胞外囊泡停靠在质膜上。Rala在许多系统中被认为是锚定依赖性生长和肿瘤转移的特异性调节因子，因此，我们的数据将整合素调控膜运输与肿瘤生长和转移联系在一起。我们现在建议研究整合素控制胞吐途径的机制，并研究其在细胞运动中的作用。具体地说，我们将通过鉴定介导Rala整合素激活的相关鸟核苷酸交换因子来阐明整合素在脂筏排出过程中调节Rala的机制，并进一步确定激活机制。我们将类似地确定介导Arf6激活的交换因素并研究其机制。最后，我们将阐明整合素调节的脂筏运输在细胞运动中的作用，特别是是否存在通过相同途径对脂筏运输的空间受限调节，以及它如何促进定向的细胞运动。这项工作将有助于我们理解一条对细胞行为至关重要的途径，也是调控癌症转移的关键途径。 公共卫生相关性：整合素信号是控制细胞生长、迁移、组织组织和形态形成的基本细胞调控机制之一。这些途径的缺陷会导致免疫缺陷、自身免疫性疾病、出生缺陷和癌症，仅举几例。整合素信号介导细胞生长的锚定依赖性，这是防止癌症转移的基本机制。该项目旨在阐明整合素调节脂筏泡运输的途径以及随后对细胞迁移和信号传递的影响。我们之前对这一途径的研究表明，它受到与癌症转移高度相关的基因产物的调控。因此，该项目对于理解和潜在地治疗癌症转移具有直接的相关性，以及对人类广泛的形态发生和迁移过程的重要影响。