权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

P21活化激酶在细胞-细胞和细胞-基质粘附信号转导中的作用摘要多细胞生物的发育和功能，组织形成以及对损伤和感染依赖于细胞彼此之间以及细胞与细胞外基质之间紧密协调的粘附。这些过程在很大程度上是通过两个家族的粘附受体介导的：主要负责细胞-基质粘附，而钙粘蛋白是细胞-细胞粘附的核心。粘连我们的初步数据表明，II型p21激活激酶（PAKs），一组丝氨酸- 苏氨酸激酶使用一系列机制来影响细胞-基质粘附和细胞-细胞粘附。的调节两种粘附系统的能力使PAK成为协调细胞粘附的中心参与者动力学该建议旨在了解这种调节的功能，细胞和分子基础。到解决他们如何控制细胞-基质和细胞-细胞粘附，我们提出了一个结构，生化，和细胞方法。在目的1中，我们检验了PAK与整联蛋白胞质尾区的直接结合粘附受体调节基质粘附和/或PAK信号传导。我们将进行广泛的研究采用结构、生物物理、生物化学和细胞生物学方法。这将使我们能够全面了解整合素粘附受体如何结合PAK丝氨酸-苏氨酸激酶，这种相互作用对细胞信号传导、粘附、运动性和侵袭的功能性后果。在目标2中，我们测试假设靶向细胞-细胞接触的PAK磷酸化β-连环蛋白，触发粘附转换，单个细胞从上皮岛逃逸。我们将确定PAK驱动殖民地的机制，逃逸，以及PAK调节β-连环蛋白的结构基础。最后，我们将测试PAK的角色是否在细胞-细胞和细胞-ECM粘附中是相关的。我们提出的工作将定义PAK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-细胞粘附之间的相互联系。