From the Curriculum in Genetics and Molecular Biology,; Lineberger Comprehensive Cancer Center.
Lineberger Comprehensive Cancer Center,; Curriculum in Toxicology.
J Biol Chem. 2013 Sep 6;288(36):26301-26310. doi: 10.1074/jbc.M113.466086. Epub 2013 Jul 26.
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.
受体酪氨酸激酶样孤儿受体 2(Ror2)的表达已在越来越多的肿瘤类型中被鉴定出来,并且已知作为 Wnt 信号级联的重要介质发挥作用。在这项研究中,我们旨在阐明 Ror2 在肾细胞癌(RCC)背景下与 Wnt 途径的相互作用。对原发性人 RCC 肿瘤中 Ror2 表达的检查显示与几种 Wnt 信号基因,包括经典反馈靶基因 Axin2 存在显著相关性。我们提供的证据表明,Ror2 表达通过增加β-连环蛋白的信号池导致经典 Wnt 信号的部分激活状态,从而在肾细胞和肾癌细胞来源的细胞中增强 Wnt3a 刺激后的下游靶基因。此外,用 siRNA 或 dickkopf 抑制低密度脂蛋白受体相关蛋白 6(LRP6)均降低了对 Wnt3a 刺激的反应,但与 Ror2 表达相关的增加的β-连环蛋白池没有变化,表明 LRP6 辅助因子募集对于 Wnt3a 诱导的信号是必需的,但它不参与 Ror2 对β-连环蛋白信号的影响。这些结果突出了 Ror2 在向可溶性β-连环蛋白传递紧张信号以稳定可溶性β-连环蛋白并为 RCC 中 Wnt3a 外源性信号的增强反应能力创造准备状态方面的新作用。
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