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CELL ADHESION IN TISSUE MORPHOGENESIS

组织形态发生中的细胞粘附

基本信息

批准号：
6375826
负责人：
WILLIAM G. CARTER
金额：
$ 33.14万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 2003-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6375826
关键词：
cell adhesion collagen complementary DNA gene induction /repression gene mutation human tissue integrins intermolecular interaction laboratory mouse laboratory rabbit laminin monoclonal antibody oligonucleotides polymerase chain reaction protooncogene site directed mutagenesis tissue /cell culture

项目摘要

DESCRIPTION: Adhesion of epithelial basal cells to the basement membrane (BM) is required for maintenance of a proliferative, undifferentiated phenotype. To understand the mechanism of this adhesion requirement, we characterized ligands, receptors, and signaling proteins involved in adhesion of cultured human foreskin keratinocytes (HFKs) to the BM: (I) Laminin 5 (epiligrin) is the primary adhesive ligand in epithelial BMs of both homeostatic tissue and wound sites. It is synthesized by HFKs in wound sites. (ii) Integrin alpha-6-beta-4 in hemidesmosome-like stable anchoring contacts (SACs) and integrin alpha-3-beta-1 in focal adhesions (FAs) are adhesion receptors for laminin-5. Epithelial cells anchor to laminin 5 via alpha-6-beta-4 in homeostatic epidermis and migrate via alpha-3-beta-1 in wound sites. Integrin alpha-2-beta-1 also functions in wound repair by interacting with collagen exposed in wound sites. (iii) Phosphorylation of a tyrosine residue(s) on a new membrane-associated signaling protein, p80, is the first detectable signaling event resulting from de-attachment of HFKs from laminin 5 via alpha-6-beta-4. In contrast, ligation of alpha-2-beta-1 and alpha-3-beta-1 regulates phosphorylation of FA kinase (FAK). Synchronization of the anchorage and migratory functions to avoid interference in wound activation is regulated by receptor cross-talk. We hypothesize, that differences in cell adhesion induced by laminin 5 verses collagen results in altered phosphorylation of p80 and FAK, DNA synthesis and differentiation. We propose to: characterize p80 and its role in cell adhesion, define the mechanisms of regulatory cross-talk between the beta-1 and beta-4 receptors, and analyze the promoter of the LAMA3 gene to identify sequences responsible for transcriptional control in response to cell adhesion. these results will define the molecular mechanism through which cell adhesion regulates gene expression and wound repair in epithelium.

描述：上皮性基底细胞与基底膜的黏附 (BM)是维持增殖的、未分化的表型。为了理解这种附着力要求的机理，我们描述了参与的配体、受体和信号蛋白体外培养的人包皮角质形成细胞与骨髓的黏附：(I) 层粘连蛋白5是上皮性骨髓间充质干细胞的主要黏附配体。包括动态平衡组织和伤口部位。它是由HFKs在伤口中合成的网站。(Ii)整合素α-6-β-4在半桥粒样稳定锚定中局灶性粘连(FA)中的接触蛋白(SAs)和整合素α-3-β-1 层粘连蛋白-5的黏附受体。上皮细胞通过层粘连蛋白5锚定 α-6-β-4在动态平衡的表皮中，并通过α-3-β-1在伤口处。整合素α-2-β-1也通过以下途径在伤口修复中发挥作用与伤口处暴露的胶原蛋白相互作用。(Iii)磷酸化新的膜相关信号蛋白p80上的酪氨酸残基(S)，是第一个可检测到的信号事件，由HFK的脱附引起从层粘连蛋白5到α-6-β-4。相反，α-2-β-1的结扎而α-3-β-1调节FAK的磷酸化。锚定和移位功能同步，以避免对伤口激活的干扰受受体串扰的调节。我们假设，层粘连蛋白5诱导的细胞黏附与胶原蛋白导致p80和FAK的磷酸化改变，DNA合成和差异化。我们建议：表征p80及其在细胞中的作用粘附性，定义了β-1之间的调节串扰机制和β-4受体，并分析LAMA3基因的启动子以鉴定负责细胞反应的转录调控的序列粘附力。这些结果将定义分子机制，通过细胞黏附调节上皮细胞基因表达和创伤修复。