Intracellular signaling and endocytosis of the growth factor midkine

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。

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.