National Engineering Laboratory for Antitumor Protein Therapeutics; Beijing Key Laboratory for Protein Therapeutics, Beijing, China.
Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):e126-34. doi: 10.1161/ATVBAHA.112.247502. Epub 2012 Jun 28.
Cell surface nucleolin (NCL) plays fundamental roles in tumor angiogenesis. However, the mechanism underlying its surface translocation remains obscure. The present study discovered that heat shock cognate 70 (Hsc70) is essential in both the surface translocation and the angiogenic function of NCL.
We identified that Hsc70 interacted with NCL in endothelial cells via the peptide-binding domain of Hsc70 and the RNA-binding domain of NCL. Functional knockdown of Hsc70 remarkably inhibited the expression of surface NCL, which was rescued by wild-type Hsc70 rather than its truncations. Phosphorylation of NCL by either protein kinase C-ξ or casein kinase 2 mediated its interaction with Hsc70 and the surface expression. Hsc70 regulated NCL translocation via stabilizing NCL and enhancing its interaction with nonmuscle myosin heavy chain 9. Moreover, Hsc70 was associated with NCL-induced endothelial cell migration and tubule formation in vitro and angiogenesis in both matrigel plugs and xenograft tumors. Tissue array analysis revealed that the expression levels of NCL and Hsc70 were intimately correlated in human lung adenocarcinomas.
Our study demonstrates that Hsc70 is a prerequisite for the surface translocation and angiogenic function of NCL, which suggests strategies to target both Hsc70 and NCL for more effective antiangiogenic therapies.
细胞表面核仁素（NCL）在肿瘤血管生成中发挥着重要作用。然而，其表面易位的机制仍不清楚。本研究发现热休克同源物 70（Hsc70）在 NCL 的表面易位和血管生成功能中是必不可少的。
我们鉴定出 Hsc70 通过 Hsc70 的肽结合结构域和 NCL 的 RNA 结合结构域与内皮细胞中的 NCL 相互作用。Hsc70 的功能敲低显著抑制了表面 NCL 的表达，而野生型 Hsc70 而不是其截断物可挽救该表达。蛋白激酶 C-ξ或酪蛋白激酶 2 对 NCL 的磷酸化介导了其与 Hsc70 的相互作用以及表面表达。Hsc70 通过稳定 NCL 并增强其与非肌球蛋白重链 9 的相互作用来调节 NCL 易位。此外，Hsc70 与 NCL 诱导的内皮细胞迁移和小管形成以及基质胶塞和异种移植肿瘤中的血管生成有关。组织阵列分析表明，人肺腺癌中 NCL 和 Hsc70 的表达水平密切相关。
我们的研究表明 Hsc70 是 NCL 表面易位和血管生成功能的前提，这表明针对 Hsc70 和 NCL 的策略可用于更有效的抗血管生成治疗。
