Intracellular signaling and endocytosis of the growth factor midkine

生长因子中期因子的细胞内信号传导和内吞作用

• 批准号: 14580647
• 负责人: KADOMATSU Kenji
• 金额: $ 2.3万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580647/
• 关键词: midkine; LRP; Nucleolin; nuclear targeting; growth factor; LDL receptor; proteasome; lysosome; nucleolin; PTPS; アポトーシス

This study has been aimed to elucidate the role(s) of endocytosed midkine (MK), a heparin-binding growth factor. MK is implicated in cancer development, neural survival, and inflammation. One of its receptors is LDL receptor-related protein (LRP), a member of the LDL receptor family. We demonstrated in this study that LRP is responsible for MK endocytosis, endocytosed MK binds to the nucleo-cytoplasmic shuffle protein nucleolin, and the nucleolin-bound MK enters the nucleus. This nuclear targeting by MK is needed for MK-mediated cell survival. We further clarified that the nuclear targeting MK is degraded by the proteasome system. Thus, proteasome inhibitors promote MK stability in the nucleus, and cytoplasmically expressed MK is polyubiquitinated. The N-terminal half domain of MK is important for proteasome-mediated degradation, while the C-terminal half domain is sufficient for nuclear localization. In summary, this study has revealed an important biological function of endocytosed nuclear targeting MK, i.e. anti-apoptosis, and a degradation mechanism of an endocytosed growth factor. We also report some important findings as to MK and cancer, including validity as a tumor marker as well as a molecular target for cancer therapy.

本研究旨在阐明内吞中期因子（MK）的作用，MK是一种肝素结合生长因子。MK与癌症发展、神经存活和炎症有关。其受体之一是LDL受体相关蛋白（LRP），LDL受体家族的成员。我们在这项研究中证明，LRP是负责MK内吞，内吞的MK结合到核质洗牌蛋白核仁素，和核仁素结合MK进入细胞核。MK介导的细胞存活需要MK的这种核靶向作用。我们进一步阐明了核靶向MK被蛋白酶体系统降解。因此，蛋白酶体抑制剂促进MK在细胞核中的稳定性，并且细胞质表达的MK是多泛素化的。MK的N端半结构域对于蛋白酶体介导的降解是重要的，而C端半结构域对于核定位是足够的。总之，本研究揭示了内吞核靶向MK的重要生物学功能，即抗凋亡，以及内吞生长因子的降解机制。我们还报告了一些关于MK和癌症的重要发现，包括作为肿瘤标志物以及癌症治疗的分子靶点的有效性。

项目成果

Uchimura et al.: "Functional analysis of the chondroitin 6-sulfotransferase gene in relation to lymphocyte subnonulations brain development and oversulfated chondroitin sulfates"J. Biol. Chem.. 277. 1443-1450 (2002)

Uchimura 等人：“软骨素 6-磺基转移酶基因与淋巴细胞亚细化、大脑发育和过硫酸软骨素硫酸盐相关的功能分析”J.

S Ikematsu et al.: "Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas"Br.J.Cancer. 88. 1522-1526 (2003)

S Ikematsu 等人：“血液中期因子水平升高与人类神经母细胞瘤不良预后因素的相关性”Br.J.Cancer。

N Suzuki et al.: "Proteasomal degradation of the nuclear targeting growth factor midkine."J.Biol.Chem.. (In press).

N Suzuki 等人：“核靶向生长因子中期因子的蛋白酶体降解。”J.Biol.Chem..（正在出版）。

S Ikematsu et al.: "Correlation of elebated level of blood midkine with poor prognostic factors of hyman neuroblastomas."Br.J.Cancer. 88. 1522-1526 (2003)

S Ikematsu 等人：“血液中期因子水平升高与海曼神经母细胞瘤不良预后因素的相关性。”Br.J.Cancer。

Suzuki, N., Shibata, Y, Urano, T., Murohara, T., Muramatsu, T., Kadomatsu K.: "Proteasomal degradation of the nuclear targeting growth factor midkine."J.Biol.Chem.. (In press.).

Suzuki, N.、Shibata, Y、Urano, T.、Murohara, T.、Muramatsu, T.、Kadomatsu K.：“核靶向生长因子中期因子的蛋白酶体降解。”J.Biol.Chem..（出版中）