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Molecular Basis of ILK/PINCH Function in Cell Adhesion

ILK/PINCH 细胞粘附功能的分子基础

基本信息

批准号：
8235954
负责人：
JUN QIN
金额：
$ 38.86万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235954
关键词：
Actins Adhesions Adhesives Binding Biochemical Blood Circulation C-terminal Cardiac Cell Adhesion Cell Adhesion Molecules Cell Shape Cell Survival Cell physiology Cell-Matrix Junction Cells Cellular biology Clinical Clinical Trials Collaborations Complex Cytoplasmic Tail Cytoskeleton Data Dilated Cardiomyopathy Disease Extracellular Domain Extracellular Matrix Extracellular Matrix Proteins Family Focal Adhesions Functional disorder G Actin Genetic Goals Heart Heart Diseases Heart Injuries Heart failure Human Integrin Binding Integrins Investigation LIM Domain LIMS1 gene Lead Learning Life Link Mechanics Mediating Methods Microfilaments Modeling Molecular Mus Mutate Mutation Myocardial Infarction NMR Spectroscopy Nature Pathologic Processes Pathway interactions Patients Peptides Phase Physiological Processes Play Process Protein Array Protein Binding Protein Dynamics Proteins Recruitment Activity Regulation Reporting Role Scientist Sequence Alignment Series Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Specificity Stress Fibers Structure Tail Testing Therapeutic Effect Time adhesion process base cardiac repair cell assembly cell motility design follow-up human disease in vivo insight integrin-linked kinase link protein migration mouse model multidisciplinary mutant novel polymerization protective effect protein complex receptor binding research study spatiotemporal three dimensional structure thymosin beta(4)

项目摘要

The attachment of cells to extracellular matrix (ECM) is crucial for a variety of physiological and pathological processes. This interaction (cell adhesion) is mediated primarily by integrins, a group of heterodimeric transmembrane receptors that bind to ECM proteins via their extracellular domains. Upon ECM engagement, integrins cluster and transduce signals into intracellular compartment leading to the formation of large protein complexes called focal adhesions (FAs) that connect integrin cytoplasmic tails (CTs) to the actin cytoskeleton. This latter step, i.e., the formation of FAs and their linkage to actin, promotes firm cell adhesion. Furthermore, it allows regulation of dynamic adhesive processes such as cell spreading and migration. Our long term goal is to obtain a detailed molecular understanding of FAs and to elucidate how they are connected to actin and modulated during various adhesive processes. To this end, we have been focusing on a major component of FAs - integrin-linked kinase (ILK). Originally discovered as an integrin linking protein that binds to integrin ¿ CTs, ILK has been established as a multifunctional protein that transmits diverse mechanical and biochemical signals between integrins and actin. A key initial step for ILK function is its tight binding to PINCH - a LIM- containing adaptor. This interaction not only promotes the localization of ILK to integrin adhesion sites but also creates a stable platform that harbors many proteins to regulate dynamic FA assembly and diverse signaling pathways. Over the past several years, we have made a major progress towards building a molecular landscape of the ILK/PINCH network and showed how it functions in a spatiotemporal manner in various cellular processes. In collaboration with clinical scientists, we have also shown that the ILK/PINCH complex is abnormally elevated in failing human hearts, suggesting its direct involvement in cardiac dysfunction. Coincidently, a recent study in mice has shown that a G-actin sequestering peptide, thymosin beta-4 (tb4), may repair cardiac damage by modulating the ILK/PINCH-mediated cell migration and survival. While this has led to widespread follow-up investigations and the launching of a tb4-based phase1A clinical trial on treating heart injury patients, the underlying molecular mechanism remains obscure. In preliminary investigation, we have discovered a novel ILK/PINCH-mediated integrin-actin linkage that may be crucial for cell migration and survival. This linkage appears to be dynamically regulated by tb4. In the next phase of our study, we will use multidisciplinary structural/functional approach to vigorously investigate this linkage and its regulation by tb4. The studies will lead to a new paradigm for understanding the ILK/PINCH-mediated cell adhesion. They will also impact on the tb4-based therapy of cardiac disorder and possibly other diseases.

细胞与细胞外基质（ECM）的附着在多种生理和病理中起着至关重要的作用