PHYSIOLOGICAL MECHANISMS OF INTEGRIN AFFINITY MODULATION

整合素亲和力调节的生理机制

• 批准号: 6030689
• 负责人: Timothy E O'Toole
• 金额: $ 23.91万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030689
• 关键词: activation product; biological signal transduction; cell adhesion; cell cell interaction; chemical binding; chimeric proteins; conformation; crosslink; cytokine receptors; cytoplasm; extracellular matrix; fibrinogen; gene expression; human tissue; hybrid cells; integrins; interleukin 2; leukocyte adhesion molecules; ligands; platelets; protein structure function; tissue /cell culture; transcription factor; transfection; yeasts

DESCRIPTION (Adapted from investigator's abstract): Blood cells such as platelets, lymphocytes and neutrophils exert their physiological function through adhesive interactions with the extracellular matrix or with other cells. The integrins, a family of transmembrane alpha, beta heterodimers which mediate the adhesion of many of these cell types, are notable for their dynamic regulation. In response to external stimuli, integrins upregulate ligand binding affinity and alter cellular adhesiveness. Preliminary data suggest that integrin "activation" or affinity modulation involves cell- specific signalling through integrin cytoplasmic domains. In this proposal, the PI will elucidate this physiological pathway. First, he will identify alpha and beta subunit cytoplasmic residues which are involved. Using extracellular alphaIIb, beta3 as a reporter group, he will generate variant cytoplasmic domains, transfect these constructs into heterologous cells and analyze their ability to bind antibody or protein ligands. Second, he will examine the effect of overexpression of integrin cytoplasmic domains on physiological activation mechanisms. Chimera consisting of the extracellular and transmembrane regions of the IL-2 receptor joined to specific integrin cytoplasmic domains have been obtained. These constructs will be co-transfected with constitutively active integrins and the inhibitory effect on binding analyzed. Finally, he will attempt to identify hypothetical cytosolic factors which interact with integrin cytoplasmic domains. Novel factors will be isolated and identified in crosslinking studies utilizing the inhibitory chimera identified above, or by regenerating the GAL4 transcription factor in a two hybrid system. Defining the mechanisms of affinity modulation is crucial to understanding the role of integrins in the physiology and pathology of blood cells.

描述（改编自研究者摘要）：血细胞如

项目成果

The WD protein Rack1 mediates protein kinase C and integrin-dependent cell migration.

WD 蛋白 Rack1 介导蛋白激酶 C 和整合素依赖性细胞迁移。

• DOI: 10.1242/jcs.114.9.1691
• 发表时间: 2001
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Buensuceso,CS;Woodside,D;Huff,JL;Plopper,GE;O'Toole,TE
• 通讯作者: O'Toole,TE