FUNCTIONAL CHARACTERIZATION OF CYTOPLASMIC DOMAIN OF ALPHAPDGF RECEPTOR

αPDGF 受体细胞质域的功能表征

• 批准号: 3853541
• 负责人: S A AARONSON
• 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/3853541
• 关键词: antireceptor antibody; biological signal transduction; enzyme mechanism; enzyme structure; growth factor receptors; human tissue; mutant; phosphatidylinositols; phospholipase C; phosphorylation; platelet derived growth factor; point mutation; protein kinase; protein structure function; protein tyrosine kinase; second messengers; site directed mutagenesis

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells. Two types (alpha and beta) of PDGF receptor have been cloned and sequenced. The ligand-binding region of the PDGF receptor is in the extracellular domain, which consists of five immunoglobulin-like regions. The cytoplasmic region of the PDGF receptor contains sequences homologous to other tyrosine kinases. The kinase sequences are interrupted by the kinase insert (KI) domain. The interaction of PDGF with its receptor causes some rapid changes in the cell, which include the activation of the receptor kinase activity, stimulation of several second messenger pathways and initiation of DNA synthesis. Both of the major in vivo and in vitro phosphorylation sites of the beta-PDGF receptor have been identified. We are studying the role of these phosphorylation sites of the alpha-PDGF receptor in signal transduction. Several point mutations of the alpha-PDGF receptor have been generated by site-directed mutagenesis. Mutation of tyrosine 731 or 742 in the KI domain does not impair PDGF-induced tyrosine phosphorylation of the receptor or of an in vivo substrate, PLC-gamma. However, both lesions markedly impair receptor association with PI-3 kinase. Anti-P-Tyr antibody recoverable PI-3 kinase was also dramatically reduced in PDGF-stimulated cells expressing either mutant receptor. Since neither mutation abolished PDGF-induced mitogenesis or chemotaxis, we conclude that alpha-PDGF receptor-associated PI-3 kinase activity is not required for either of these major PDGF signalling functions.

血小板衍生生长因子（PDGF）是一种有效的有丝分裂原