Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
Oncogene. 2011 Feb 3;30(5):535-47. doi: 10.1038/onc.2010.427. Epub 2010 Sep 27.
von Hippel-Lindau (VHL) tumor suppressor loss is associated with renal cell carcinoma (RCC) pathogenesis. Meanwhile, aberrant activation of the insulin-like growth factor-I (IGF-I) signaling has been implicated in the development of highly invasive metastatic RCC. However, the link between VHL inactivation and RCC invasiveness is still unexplored. Here, we show that the receptor for activated C kinase 1 (RACK1) is a novel pVHL-interacting protein. pVHL competes with IGF-I receptor (IGF-IR) for binding to RACK1 thus potentially modulating the downstream IGF-I signal pathway. Upon IGF-I stimulation, pVHL-deficient RCC cells exhibit increased RACK1/IGF-IR binding and increased IGF-IR tyrosine kinase activity. pVHL-deficient RCC cells also demonstrate elevated PI3K/Akt signaling and matrix metalloproteinase-2 activity that culminates in enhanced cellular invasiveness, which can be partially suppressed by RACK1 small interfering RNA. Domain mapping analysis showed that the pVHL α-domain and the RACK1 WD 6-7 domains are critical for the interaction. Additionally, the RACK1 expression level is not regulated by pVHL expression status, suggesting that pVHL modifies RACK1 functions independent of the VHL/elongin E3 ubiquitin ligase complex. Our data indicate that RACK1 serves as a direct mediator between loss of pVHL function and enhanced IGF-IR signaling pathway in RCC.
希佩尔-林道(VHL)肿瘤抑制因子失活与肾细胞癌(RCC)的发病机制有关。同时,胰岛素样生长因子-I(IGF-I)信号的异常激活被认为与高度侵袭性转移性 RCC 的发展有关。然而,VHL 失活与 RCC 侵袭性之间的联系仍未被探索。在这里,我们表明,激活的 C 激酶 1(RACK1)受体是一种新型的 pVHL 相互作用蛋白。pVHL 与 IGF-I 受体(IGF-IR)竞争与 RACK1 的结合,从而可能调节下游 IGF-I 信号通路。在 IGF-I 刺激下,pVHL 缺陷型 RCC 细胞表现出增加的 RACK1/IGF-IR 结合和增加的 IGF-IR 酪氨酸激酶活性。pVHL 缺陷型 RCC 细胞还表现出升高的 PI3K/Akt 信号和基质金属蛋白酶-2 活性,导致细胞侵袭性增强,这可以部分被 RACK1 小干扰 RNA 抑制。结构域映射分析表明,pVHL 的α结构域和 RACK1 的 WD6-7 结构域对于相互作用至关重要。此外,RACK1 的表达水平不受 pVHL 表达状态的调节,表明 pVHL 修饰 RACK1 的功能独立于 VHL/elongin E3 泛素连接酶复合物。我们的数据表明,RACK1 作为 pVHL 功能丧失和 RCC 中 IGF-IR 信号通路增强之间的直接介导物。