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Nuclear Targeting by the Growth Factor Midkine

机译：生长因子Midkine的核靶向

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Ligand-receptor internalization has been traditionally regarded as part of the cellular desensitization system. Low-density lipoprotein receptor-related protein (LRP) is a large endocytosis receptor with a diverse array of ligands. We recently showed that LRP binds heparin-binding growth factor midkine. Here we demonstrate that LRP mediates nuclear targeting by midkine and that the nuclear targeting is biologically important. Exogenous midkine reached the nucleus, where intact midkine was detected, within 20 min. Midkine was not internalized in LRP-deficient cells, whereas transfection of an LRP expression vector restored midkine internalization and subsequent nuclear translocation. Internalized midkine in the cytoplasm bound to nucleolin, a nucleocytoplasmic shuttle protein. The midkine-binding sites were mapped to acidic stretches in the N-terminal domain of nucleolin. When the nuclear localization signal located next to the acidic stretches was deleted, we found that the mutant nucleolin not only accumulated in the cytoplasm but also suppressed the nuclear translocation of midkine. By using cells that overexpressed the mutant nucleolin, we further demonstrated that the nuclear targeting was necessary for the full activity of midkine in the promotion of cell survival. This study therefore reveals a novel role of LRP in intracellular signaling by its ligand and the importance of nucleolin in this process.
机译：传统上，配体受体内化被认为是细胞脱敏系统的一部分。低密度脂蛋白受体相关蛋白（LRP）是具有多种配体阵列的大型胞吞受体。我们最近表明，LRP结合肝素结合生长因子中期因子。在这里，我们证明LRP介导中期因子介导的核靶向，并且核靶向在生物学上很重要。外源性中期因子在20分钟内到达细胞核，在那里检测到完整的中期因子。 Midkine没有在LRP缺陷细胞中被内在化，而LRP表达载体的转染恢复了Midkine的内在化和随后的核易位。细胞质中的内源性中期因子与核仁蛋白（一种核质穿梭蛋白）结合。中期因子结合位点被映射到核仁蛋白的N末端域中的酸性段。当位于酸性段旁边的核定位信号被删除时，我们发现突变核仁素不仅在细胞质中积累，而且抑制了中期因子的核易位。通过使用过度表达突变核仁蛋白的细胞，我们进一步证明了核靶向对于中期因子在促进细胞存活中的全部活性是必需的。因此，这项研究揭示了LRP通过其配体在细胞内信号传导中的新作用以及核仁蛋白在此过程中的重要性。

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