THE ROLE OF PI-3K IN ALPHA-PDGFR-MEDIATED MITOGENIC SIGNAL TRANSDUCTION

PI-3K 在 ALPHA-PDGFR 介导的有丝分裂信号转导中的作用

• 批准号: 3774872
• 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/3774872
• 关键词: 3T3 cells; DNA replication; alcohol phosphotransferase; biological signal transduction; cell cycle proteins; chemical association; enzyme activity; enzyme mechanism; enzyme substrate; gene mutation; growth factor receptors; human tissue; mitogens; phenylalanine; phosphorylation; platelet derived growth factor; protein tyrosine kinase; transfection

In platelet-derived growth factor receptor (PDGFR), tyrosine phosphorylation of specific sites is required for association with known substrates. The tyrosine phosphorylation sites interacting with PI-3 kinase have been identified as tyrosine 731 and tyrosine 742 in human alphaPDGFR. to study the role of PI-3 kinase in the PDGFR-mediated mitogenic signal pathway, both tyrosines were mutated to phenylalanine and it was found that the double mutant receptor (Y731F/Y742F) completely blocked receptor association with PI-3 kinase. anti-P-Tyr-recoverable PI-3 kinase activity was also reduced in PDGF-stimulated cells expressing the double mutant receptor. However, mutation of these tyrosines does not impair PDGF-induced receptor kinase activity or activation of c-raf and MAP kinase protein. Furthermore, DNA synthesis in response to PDGF stimulation was unaffected by these tyrosine mutations in 32D cells. In NIH/3T3 cells, neither single-mutant (Y731F) nor double-mutant receptors impaired foci-forming activity induced by cotransfection with PDGF-AA. These results suggest that PDGFR-associated PI-3 kinase activity is not required for PDGF-induced mitogenesis or transformation signaling.

血小板衍生生长因子受体(PDGFR)中的酪氨酸 需要特定位点的磷酸化才能与已知的 底物。与PI-3相互作用的酪氨酸磷酸化位点 在人类中已鉴定为酪氨酸731和酪氨酸742 字母PDGFR。PI-3激酶在PDGFR介导的心肌细胞损伤中的作用 有丝分裂信号通路，两种酪氨酸都突变为苯丙氨酸 并发现双突变受体(Y731F/Y742F)完全 阻断PI-3激酶与受体的联系。抗P-Tyr-可回收 在PDGF刺激的细胞中，PI-3激酶活性也降低，表达 双突变受体。然而，这些酪氨酸的突变会 不影响PDGF诱导的受体激酶活性或c-RAF的激活 和MAP激酶蛋白。此外，PDGF对DNA合成的响应 32D细胞的刺激不受这些酪氨酸突变的影响。在……里面 NIH/3T3细胞，既不是单突变(Y731F)也不是双突变受体 与PDGF-AA共转染组的成灶活性降低。 这些结果表明，PDGFR相关的PI-3激酶活性不是 是PDGF诱导的有丝分裂或转化信号所必需的。