CHARACTERIZATION OF SIGNALLING PATHAYS OF THE PDGF/CSF-1 RECEPTOR

PDGF/CSF-1 受体信号通路的表征

• 批准号: 3874779
• 负责人: J H PIERCE
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874779
• 关键词: biological signal transduction; chemotaxis; colony stimulating factor; dimer; gene deletion mutation; genetic manipulation; growth factor receptors; human tissue; phosphatidylinositols; platelet derived growth factor; protein structure function; protein tyrosine kinase; receptor coupling; transposon /insertion element

Alpha and beta platelet-derived growth factor receptors (PDGFR) are encoded by two different genes and are triggered differently by the three dimeric forms of PDGF. The specific functions mediated by the products of the independent PDGF receptor-encoding genes have been investigated. By using a strategy involving introduction of expression vectors for alpha and betaPDGFR cDNAs into a naive hematopoietic cell line (32D), it has been demonstrated that each receptor independently couples with mitogenic signal transduction pathways inherently present in these cells. Both receptors can induce chemotactic responses, inositol phospholipid metabolism and [Ca 2+] mobilization. The human alphaPDGFR, like the betaPDGFR and colony stimulating factor (CSF)-1/c-fms, is interrupted by a kinase insert. In order to define the role of this region, two deletion mutants which lacked 81 (709-790) and 96 (694-790) amino acids of the 104-amino acid kinase insert have been generated. The functional characteristics of these mutants have been compared with the wild-type alphaPDGFR following introduction into the same hematopoietic cell line. Only the small deletion was capable of coupling with the mitogenic signalling pathway, phosphoinositide turnover and chemotactic response, but in a less efficient way. Furthermore, the insertion of the c-fms kinase insert into the large deletion mutant restored the biochemical and biological activities of the alphaPDGFR. These results indicate that alterations in the structural conformation of the kinase domain of the alphaPDGFR affect the multiple functions of this molecule.

α和β血小板衍生生长因子受体（PDGFR）是由 由两个不同的基因，并由三个二聚体 PDGF的形式。这些产物所介导的特定功能 已经研究了独立的PDGF受体编码基因。通过使用 涉及导入α和β-葡聚糖的表达载体的策略 将β PDGFR cDNA导入幼稚造血细胞系（32 D）， 表明每个受体独立地与促有丝分裂信号偶联， 这些细胞中固有的转导途径。两种受体都可以 诱导趋化反应、肌醇磷脂代谢和[Ca ~（2+）] 动员。人的α PDGFR，像β PDGFR和菌落 刺激因子（CSF）-1/c-fms被激酶插入物中断。在 为了确定这个区域的作用，两个缺失突变体， 104-氨基酸激酶的81（709-790）和96（694-790）个氨基酸 已生成插入。这些突变体的功能特征 引入后已与野生型alphaPDGFR进行了比较 相同的造血细胞系。只有一个小的缺失 与促有丝分裂信号通路偶联的磷酸肌醇 周转和趋化反应，但以较低的效率。 此外，将c-fms激酶插入物插入到大的 缺失突变体恢复的生化和生物活性的 α PDGFR。这些结果表明，结构的改变 α PDGFR的激酶结构域的构象影响多个 这个分子的功能。