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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：
10641867
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641867
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 Crystallography Cytoplasm Cytoplasmic Tail Cytoskeletal Modeling Data Development Disease Dissociation Enzymes Epithelial Cells Epithelium Extracellular Matrix Family Focal Adhesions Growth Impairment Individual Infection Integrin Binding Integrin Inhibition Integrins Interdisciplinary Study Interruption Invaded Investigation Island Link Malignant Neoplasms Mediating Molecular Monomeric GTP-Binding Proteins Morphology Neoplasm Metastasis Nuclear Organism 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 beta catenin cancer cell cell motility design insight member migration 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-基质粘附信号传导中的作用

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intracellular tension sensor reveals mechanical anisotropy of the actin cytoskeleton.

DOI：
10.1038/s41467-023-43612-5
发表时间：
2023-12-04
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Amiri, Sorosh;Muresan, Camelia;Shang, Xingbo;Huet-Calderwood, Clotilde;Schwartz, Martin A.;Calderwood, David A.;Murrell, Michael
通讯作者：
Murrell, Michael