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:
- 金额:$ 38.86万
- 依托单位:
- 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:
- 关键词:ActinsAdhesionsAdhesivesBindingBiochemicalBlood CirculationC-terminalCardiacCell AdhesionCell Adhesion MoleculesCell ShapeCell SurvivalCell physiologyCell-Matrix JunctionCellsCellular biologyClinicalClinical TrialsCollaborationsComplexCytoplasmic TailCytoskeletonDataDilated CardiomyopathyDiseaseExtracellular DomainExtracellular MatrixExtracellular Matrix ProteinsFamilyFocal AdhesionsFunctional disorderG ActinGeneticGoalsHeartHeart DiseasesHeart InjuriesHeart failureHumanIntegrin BindingIntegrinsInvestigationLIM DomainLIMS1 geneLeadLearningLifeLinkMechanicsMediatingMethodsMicrofilamentsModelingMolecularMusMutateMutationMyocardial InfarctionNMR SpectroscopyNaturePathologic ProcessesPathway interactionsPatientsPeptidesPhasePhysiological ProcessesPlayProcessProtein ArrayProtein BindingProtein DynamicsProteinsRecruitment ActivityRegulationReportingRoleScientistSequence AlignmentSeriesSignal PathwaySignal TransductionSiteSite-Directed MutagenesisSpecificityStress FibersStructureTailTestingTherapeutic EffectTimeadhesion processbasecardiac repaircell assemblycell motilitydesignfollow-uphuman diseasein vivoinsightintegrin-linked kinaselink proteinmigrationmouse modelmultidisciplinarymutantnovelpolymerizationprotective effectprotein complexreceptor bindingresearch studyspatiotemporalthree dimensional structurethymosin 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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('JUN QIN', 18)}}的其他基金
Cell Adhesion and Signaling in Blood and Vascular Cells
血液和血管细胞中的细胞粘附和信号传导
- 批准号:
10471908 - 财政年份:2021
- 资助金额:
$ 38.86万 - 项目类别:
Project 2- Mechanistic Role of Talin in Cellular Signaling
项目 2 - Talin 在细胞信号转导中的机制作用
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10471913 - 财政年份:2021
- 资助金额:
$ 38.86万 - 项目类别:
Project 2- Mechanistic Role of Talin in Cellular Signaling
项目 2 - Talin 在细胞信号转导中的机制作用
- 批准号:
10268698 - 财政年份:2021
- 资助金额:
$ 38.86万 - 项目类别:
Cell Adhesion and Signaling in Blood and Vascular Cells
血液和血管细胞中的细胞粘附和信号传导
- 批准号:
10661620 - 财政年份:2021
- 资助金额:
$ 38.86万 - 项目类别:
Project 2- Mechanistic Role of Talin in Cellular Signaling
项目 2 - Talin 在细胞信号转导中的机制作用
- 批准号:
10661636 - 财政年份:2021
- 资助金额:
$ 38.86万 - 项目类别:
Signaling Networks of Nuclear Receptor Transcriptional Crosstalk in Lung Cancer
肺癌核受体转录串扰的信号网络
- 批准号:
8898227 - 财政年份:2014
- 资助金额:
$ 38.86万 - 项目类别:
Signaling Networks of Nuclear Receptor Transcriptional Crosstalk in Lung Cancer
肺癌核受体转录串扰的信号网络
- 批准号:
9120927 - 财政年份:2014
- 资助金额:
$ 38.86万 - 项目类别:
Signaling Networks of Nuclear Receptor Transcriptional Crosstalk in Lung Cancer
肺癌核受体转录串扰的信号网络
- 批准号:
8785287 - 财政年份:2014
- 资助金额:
$ 38.86万 - 项目类别:
Molecular Basis of ILK/PINCH Function in Cell Adhesion
ILK/PINCH 细胞粘附功能的分子基础
- 批准号:
7806538 - 财政年份:2009
- 资助金额:
$ 38.86万 - 项目类别:
Molecular Basis of ILK/PINCH Function in Cell Adhesion
ILK/PINCH 细胞粘附功能的分子基础
- 批准号:
7669735 - 财政年份:2009
- 资助金额:
$ 38.86万 - 项目类别:
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