P21-activated kinases in cell-cell and cell-matrix adhesion signaling

细胞间和细胞基质粘附信号转导中的 P21 激活激酶

基本信息

批准号：
10250504
负责人：
Titus Jonathon Boggon
金额：
$ 42.07万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250504
关键词：
Adaptor Signaling Protein Address Adhesions Affect Binding Biochemical Biological Biophysics Cadherins Cell Adhesion Cell Shape Cell physiology Cell-Cell Adhesion Cell-Matrix Junction Cells Complex Crystallization Cytoplasmic Tail Cytoskeletal Modeling Data Development Disease Dissociation Enzymes Epithelial Epithelial Cells Extracellular Matrix Family Focal Adhesions Growth Growth and Development function Impairment Individual Infection Integrin Binding Integrins Interdisciplinary Study Interruption Investigation Island Link Malignant Neoplasms Mediating Molecular Monomeric GTP-Binding Proteins Morphology Neoplasm Metastasis Nuclear Organism Out-Migrations PAK6 gene Phosphorylation Phosphotransferases Point Mutation Positioning Attribute Process Protein Kinase Protein-Serine-Threonine Kinases Proteins Regulation Role Signal Transduction Structure System Testing Tissues Work adhesion receptor base beta catenin cancer cell cell motility design insight member mutant novel overexpression p21 activated kinase protein protein interaction receptor binding response to injury scaffold transcription factor

项目摘要

P21-activated kinases in cell-cell and cell-matrix adhesion signaling ABSTRACT The development and functioning of multicellular organisms, tissue formation, and responses to injury and infection rely on tightly coordinated adhesion of cells to one another, and of cells to the extracellular matrix. These processes are mediated in large part through the action of two families of adhesion receptors: the integrins which are principally responsible for cell-matrix adhesion, and the cadherins which are central to cell-cell adhesion. Our preliminary data suggest that the type-II p21-activated kinases (PAKs), a group of serine- threonine kinases, use a range of mechanisms to influence cell-matrix adhesion and cell-cell adhesion. The ability to regulate both adhesion systems places the PAKs as central players in coordination of cell adhesion dynamics. This proposal aims to understand the functional, cellular and molecular basis for this regulation. To address how they control cell-matrix and cell-cell adhesions we propose a combination of structural, biochemical and cellular approaches. In Aim 1 we test the hypothesis that Direct binding of PAK to cytoplasmic tails of integrin adhesion receptors regulates matrix adhesion and/or PAK signaling. We will conduct an extensive study employing structural, biophysical, biochemical and cell biological approaches. This will allow us to comprehensively understand how integrin adhesion receptors bind PAK serine-threonine kinases, and the functional consequences of such interactions on cell signaling, adhesion, motility and invasion. In Aim 2 we test the hypothesis that PAK targeted to cell-cell contacts phosphorylates b-catenin, triggering adhesion turnover and escape of individual cells from epithelial islands. We will determine the mechanisms by which PAKs drive colony escape, and the structural basis for PAK regulation of β-catenin. Finally, we will test whether the roles of PAKs in cell-cell and cell-ECM adhesion are linked. Our proposed work will define how PAKs regulate both integrin- mediated cell-matrix adhesion, and β-catenin-associated cell-cell adhesion, and therefore will provide new understanding of interconnections between cell-matrix and cell-cell adhesion via the type-II PAKs.

细胞间和细胞基质粘附信号转导中的 P21 激活激酶抽象的多细胞生物的发育和功能、组织形成以及对损伤和损伤的反应感染依赖于细胞之间以及细胞与细胞外基质的紧密协调的粘附。这些过程在很大程度上是通过两个粘附受体家族的作用介导的：整合素主要负责细胞-基质粘附，而钙粘蛋白则对细胞-细胞至关重要我们的初步数据表明，II 型 p21 激活激酶 (PAK) 是一组丝氨酸- 苏氨酸激酶利用一系列机制影响细胞-基质粘附和细胞-细胞粘附。调节两个粘附系统的能力使 PAK 成为协调细胞粘附的核心参与者该提案旨在了解这种调节的功能、细胞和分子基础。解决它们如何控制细胞基质和细胞细胞粘附，我们提出了结构、生化的结合在目标 1 中，我们测试了 PAK 与整合素细胞质尾部直接结合的假设。粘附受体调节基质粘附和/或 PAK 信号传导。采用结构、生物物理、生物化学和细胞生物学方法。全面了解整合素粘附受体如何结合PAK丝氨酸-苏氨酸激酶，以及在目标 2 中，我们测试了这种相互作用对细胞信号传导、粘附、运动和侵袭的功能影响。假设 PAK 靶向细胞与细胞接触，磷酸化 β-连环蛋白，引发粘附周转，我们将确定 PAK 驱动集落的机制。逃逸以及 PAK 调节 β-catenin 的结构基础最后，我们将测试 PAK 是否发挥作用。我们提出的工作将定义 PAKs 如何调节整合素。介导的细胞-基质粘附和β-连环蛋白相关的细胞-细胞粘附，因此将提供新的通过 II 型 PAK 了解细胞-基质和细胞-细胞粘附之间的互连。