Structural and functional analysis of ligand-induced polyubiquitination of platelet-derived growth factor receptor

配体诱导的血小板衍生生长因子受体多聚泛素化的结构和功能分析

• 批准号: 07557222
• 负责人: MORI Seijiro
• 金额: $ 0.64万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557222/
• 关键词: platelet-derived growth factor receptor; polyubiquitination; ubiquitin; proteasome; 血小板由来増殖因子; 受容体チロシンキナーゼ

We have previously reported that the platelet-derived growth factor (PDGF) receptors are polyubiquitinated as a consequence of ligand binding, and have suggested that the ligand-induced receptor ubiquitination plays a negative regulatory role in mitogenic signaling of the receptor, possible by promoting the efficient degradation of the ligand-activated receptor. In the present study, we have showed that, in addition to the PDGF receptors, the receptors for epidermal growth factor, fibroblast growth factor, and colony-stimulating factor-1, are also ubiquitinated after ligand stimulation, suggesting that the ligand-induced receptor ubiquitination is a general phenomenon observed in most of the monomeric receptor tyrosine kinases. Furthermore, we have proved that the ligand-activated and polyubiquitinated PDGF receptor is quickly degraded by 26S proteasomes inside the cells, thereby intracellular signaling by the receptor is terminated. Our present study establishes the biological significance of a novel mechanism for down-regulation of signal transduction by the receptor, namely, ligand-induced ubiquitination and subsequent proteasomal degradation of the monomeric receptor tyrosine kinases.

我们以前曾报道，血小板衍生生长因子（PDGF）受体是多泛素化的配体结合的结果，并建议，配体诱导的受体泛素化在有丝分裂信号的受体，可能通过促进配体激活的受体的有效降解发挥负调控作用。在本研究中，我们已经表明，除了PDGF受体，表皮生长因子，成纤维细胞生长因子和集落刺激因子-1的受体，也是泛素化配体刺激后，这表明配体诱导的受体泛素化是一种普遍现象，在大多数单体受体酪氨酸激酶。此外，我们已经证明，配体激活和多泛素化的PDGF受体被细胞内的26 S蛋白酶体快速降解，从而终止受体的细胞内信号传导。我们目前的研究建立了一个新的机制下调受体的信号转导，即配体诱导的泛素化和随后的蛋白酶体降解的单体受体酪氨酸激酶的生物学意义。

项目成果

Seijiro Mori: "Ligand-activated platelet-derived growth factor beta-receptor is degraded through proteasome-dependent proteolytic pathway" Biochem.Biophys.Res.Commun.217. 224-229 (1995)

Seijiro Mori：“配体激活的血小板衍生生长因子 β 受体通过蛋白酶体依赖性蛋白水解途径降解”Biochem.Biophys.Res.Commun.217。

森 聖二郎: "Ligand-activated platelet-derived growth factor β-receptor is degraded through proteasome-dependent proteolytic pathway" Biochem.Biophys.Res.Commun.217. 224-229 (1995)

Seijiro Mori：“配体激活的血小板衍生生长因子 β-受体通过蛋白酶体依赖性蛋白水解途径降解”Biochem.Biophys.Res.Commun.217 (1995)。

森 聖二郎: "Ligand-induced polyubiquitination of receptor tyrosine kinases" Biochem.Biophys.Res.Commun.213. 32-39 (1995)

Seijiro Mori：“受体酪氨酸激酶的配体诱导的多泛素化”Biochem.Biophys.Res.Commun.213（1995）。

森, 聖二郎: "Ligand-induced polyubiquitination of receptor tyrosine kinases" Biochem. Biophys. Res. Commun.213. 32-39 (1995)

Mori, Seijiro：“受体酪氨酸激酶的配体诱导的多泛素化”Biochem。 Commun.213 (1995)。

森 聖二郎: "Degradation process of ligand-stimulated platelet-derived growth factor β-receptor involves ubiquitin-proteasome proteolytic pathway" J.Biol.Chem.270. 29447-29452 (1995)

Seijiro Mori：“配体刺激的血小板衍生生长因子 β-受体的降解过程涉及泛素蛋白酶体蛋白水解途径”J.Biol.Chem.270（1995）。