CELL ADHESION IN TISSUE MORPHOGENESIS

组织形态发生中的细胞粘附

• 批准号: 6172174
• 负责人: WILLIAM G. CARTER
• 金额: $ 32.31万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172174
• 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

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.

上皮基底细胞与基底膜的粘附 (BM)是维持一个增殖的，未分化的 表型 为了理解这种粘附要求的机制，我们 特征性的配体、受体和信号蛋白参与 培养的人包皮角质形成细胞（HFKs）与BM的粘附：（I） 层粘连蛋白5（epiligrin）是上皮BM中的主要粘附配体， 自我平衡组织和伤口部位。 它是由伤口中的HFK合成的 网站. (ii)整合素α-6-β-4与半桥粒样稳定锚定 局部粘连（FA）中的接触蛋白（SAC）和整合素α-3-β-1是 层粘连蛋白-5的粘附受体。 上皮细胞通过以下途径锚定于层粘连蛋白5 α-6-β-4在稳态表皮中迁移，并通过α-3-β-1在稳态表皮中迁移。 伤口部位 整合素α-2-β-1也通过以下方式在伤口修复中起作用： 与伤口部位暴露的胶原蛋白相互作用。 (iii)磷酸化 一种新的膜相关信号蛋白，p80， 是由HFK的脱附引起的第一个可检测的信号传导事件 从层粘连蛋白5通过α-6-β-4。 相反，连接α-2-β-1 α-3-β-1调节FA激酶（FAK）的磷酸化。 锚定和迁移功能的同步， 创伤激活的干扰由受体串扰调节。 我们 假设层粘连蛋白5与层粘连蛋白5诱导的细胞粘附差异 胶原导致p80和FAK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，定义β-1之间的调节串扰的机制， 和β-4受体，并分析LAMA 3基因的启动子， 负责响应细胞应答的转录控制的序列 粘连 这些结果将确定分子机制， 细胞粘附调节上皮中的基因表达和创伤修复。