Kindlin-2 in Cell-Matrix Adhesion and Signaling

Kindlin-2 在细胞基质粘附和信号传导中的作用

• 批准号: 8588336
• 负责人: CHUANYUE WU
• 金额: $ 31.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588336
• 关键词: Abnormal Cell; Adhesions; Behavior; Binding; Biology; Catalytic Domain; Cell-Matrix Junction; Cytoplasmic Protein; Cytoskeleton; Defect; Dominant-Negative Mutation; Event; Extracellular Matrix; Focal Adhesions; Funding; Genetic; Goals; Growth; Hepatocyte; Integrins; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Link; Liver; Malignant Neoplasms; Mediating; Membrane; Membrane Lipids; Membrane Proteins; Molecular; Natural regeneration; Organ; PTEN gene; Pathogenesis; Pathologic Processes; Phosphatidylinositols; Phosphotransferases; Physiological; Physiological Processes; Process; Protein Binding; Proteins; Regulation; Role; Scaffolding Protein; Signal Transduction; Site; Structure; Testing; Tissues; Work; base; cell behavior; design; disorder control; human disease; improved; injury and repair; integrin-linked kinase; molecular pathology; mutant; new therapeutic target; novel strategies; phosphatidylinositol 3,4,5-triphosphate; phosphoinositide-3,4,5-triphosphate; public health relevance; receptor; tissue processing; tissue regeneration

DESCRIPTION (provided by applicant): The long-term goal of this competing renewal application is to elucidate the molecular basis underlying cell- extracellular matrix (ECM) adhesion and regulation, and the mechanism whereby they control cell behavior, tissue integrity, growth and regeneration. Recent studies by the applicant and others have demonstrated a critical role of kindlin-2 (also known as Mig-2), a widely expressed membrane-cytoskeleton junctional protein, in integrin activation and cell-ECM adhesion. How kindlin-2 regulates these processes, however, is not known. Based on findings obtained during previous project periods, the applicant hypothesizes that kindlin-2 regulates these processes through interacting with membrane lipids and protein components of cell-ECM adhesions. To test this hypothesis, he proposes studies with the following three aims. Aim 1 is to characterize the interaction of kindlin-2 with membrane lipids and assess its role in regulation of integrins and integrin-dependent processes. To this end, he will employ genetic, pharmacological and dominant negative inhibition strategies to ablate this interaction, and determine the consequences. Aim 2 is to determine the functions of kindlin-2 interactions with focal adhesion proteins in regulation of cell-ECM adhesion. He will define the sites mediating the interactions and use a "knock-in" strategy to replace wild type kindlin-2 with mutants lacking specific protein-binding activity and determine the consequences. Aim 3 is to investigate the functions of kindlin-2 and its interplay with ILK in liver structure, growth and regeneration, which are known to be regulated by ECM adhesion and ILK signaling. He will generate hepatocyte-specific kindlin-2 knockout and "knock-in" mice, in which wild type kindlin-2 is substituted with kindlin-2 mutants lacking specific binding activities, and determine contributions of kindlin-2 and its interactions to regulation of hepatocyte behavior, liver structure, growth and regeneration. These studies will fill important gaps in our understanding of the mechanism whereby cell-ECM adhesion and ECM-dependent tissue processes are regulated. Given the importance of cell-ECM adhesion in human diseases, these studies may also lead to novel approaches to control diseases associated with abnormal cell-ECM adhesion and signaling.

描述（由申请人提供）：该竞争性更新申请的长期目标是阐明细胞-细胞外基质（ECM）粘附和调节的分子基础，以及它们控制细胞行为、组织完整性、生长和再生的机制。申请人和其他人的最近研究已经证明了kindlin-2（也称为Mig-2）（一种广泛表达的膜-细胞骨架连接蛋白）在整联蛋白活化和细胞-ECM粘附中的关键作用。然而，kindlin-2如何调节这些过程尚不清楚。基于在先前项目期间获得的发现，申请人假设kindlin-2通过与细胞-ECM粘附的膜脂质和蛋白质组分相互作用来调节这些过程。为了验证这一假设，他提出了以下三个目标的研究。目的1是表征kindlin-2与膜脂质的相互作用，并评估其在调节整合素和整合素依赖性过程中的作用。为此，他将采用遗传、药理和显性负抑制策略来消除这种相互作用，并确定其后果。目的二是研究kindlin-2与黏着斑蛋白的相互作用对细胞与ECM粘附的调节作用。他将确定介导相互作用的位点，并使用“敲入”策略用缺乏特异性蛋白结合活性的突变体取代野生型kindlin-2，并确定结果。目的3：研究Kindlin-2在肝脏结构、生长和再生中的作用及其与ILK的相互作用。他将产生肝细胞特异性kindlin-2敲除和“敲入”小鼠，其中野生型kindlin-2被缺乏特异性结合活性的kindlin-2突变体取代，并确定kindlin-2及其相互作用对肝细胞行为，肝脏结构，生长和再生的调节的贡献。这些研究将填补我们理解细胞-ECM粘附和ECM依赖性组织过程调节机制的重要空白。鉴于细胞-ECM粘附在人类疾病中的重要性，这些研究也可能导致控制与异常细胞-ECM粘附和信号传导相关的疾病的新方法。

项目成果

Tenascin-X is a novel diagnostic marker of malignant mesothelioma.

Tenascin-X是恶性间皮瘤的新型诊断标记。

• DOI: 10.1097/pas.0b013e3181b6bde3
• 发表时间: 2009-11
• 期刊: The American journal of surgical pathology
• 作者: Yuan Y;Nymoen DA;Stavnes HT;Rosnes AK;Bjørang O;Wu C;Nesland JM;Davidson B
• 通讯作者: Davidson B

PINCH-2 expression in cancers involving serosal effusions using quantitative PCR.

使用定量PCR涉及浆膜积液的癌症中的捏合-2表达。

• DOI: 10.1111/j.1365-2303.2010.00757.x
• 发表时间: 2011-02
• 期刊: Cytopathology : official journal of the British Society for Clinical Cytology
• 作者: Yuan Y;Dong HP;Nymoen DA;Nesland JM;Wu C;Davidson B
• 通讯作者: Davidson B

Kindlin-2 (Mig-2): a co-activator of beta3 integrins.

• DOI: 10.1083/jcb.200710196
• 发表时间: 2008-05-05
• 期刊: The Journal of cell biology
• 作者: Ma YQ;Qin J;Wu C;Plow EF
• 通讯作者: Plow EF

Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.

Kindlin-2 控制 TGF-β 信号传导和 Sox9 表达来调节软骨形成

• DOI: 10.1038/ncomms8531
• 发表时间: 2015-07-07
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Wu, Chuanyue;Jiao, Hongli;Lai, Yumei;Zheng, Wei;Chen, Ka;Qu, Hong;Deng, Weimin;Song, Pingping;Zhu, Ke;Cao, Huiling;Galson, Deborah L.;Fan, Jie;Im, Hee-Jeong;Liu, Yujie;Chen, Ju;Chen, Di;Xiao, Guozhi
• 通讯作者: Xiao, Guozhi

Migfilin's elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via β-catenin upregulation.

Migfilin从骨关节炎的软骨细胞中消除进一步通过β-catenin上调促进了骨关节炎的表型。

• DOI: 10.1016/j.bbrc.2012.12.008
• 发表时间: 2013-01-11
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Gkretsi, Vasiliki;Papanikolaou, Vassilis;Dubos, Stephanie;Papathanasiou, Ioanna;Giotopoulou, Nikolina;Valiakou, Vaia;Wu, Chuanyue;Malizos, Konstantinos N.;Tsezou, Aspasia
• 通讯作者: Tsezou, Aspasia