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.

我们先前已经报道说，血小板衍生的生长因子（PDGF）受体是由配体结合而产生的，并提出，配体诱导的受体泛素化在受体的有丝分裂信号中起着负调控作用，可以通过促进受体的丝裂原性作用。配体激活受体的有效降解。在本研究中，我们已经表明，除了PDGF受体外，表皮生长因子，成纤维细胞生长因子和刺激性刺激因子1的受体在配体刺激后也被泛素化，这表明配体诱导的受体受体诱导的受体诱导的受体泛素化是在大多数单体受体酪氨酸激酶中观察到的一般现象。此外，我们已经证明了配体激活和多泛素化的PDGF受体很快被细胞内的26S蛋白酶体降解，从而终止受体的细胞内信号传导。我们的本研究确定了一种新型机制，即通过受体下调信号转导的下调，即配体诱导的泛素化和随后的单体受体酪氨酸激酶的蛋白酶体降解。

项目成果

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

Seijiro Mori：“配体诱导的受体酪氨酸激酶多泛素化。”

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)。