PDF(Pubmed)
Abstract：
To explore whether the p17 protein of oncolytic avian reovirus (ARV) mediates cell migration and invadopodia formation, we applied several molecular biological approaches for studying the involved cellular factors and signal pathways. We found that ARV p17 activates the p53/phosphatase and tensin homolog (PTEN) pathway to suppress the focal adhesion kinase (FAK)/Src signaling and downstream signal molecules, thus inhibiting cell migration and the formation of invadopodia in murine melanoma cancer cell line (B16-F10). Importantly, p17-induced formation of invadopodia could be reversed in cells transfected with the mutant PTENC124A. p17 protein was found to significantly reduce the expression levels of tyrosine kinase substrate 5 (TKs5), Rab40b, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), and matrix metalloproteinases (MMP9), suggesting that TKs5 and Rab40b were transcriptionally downregulated by p17. Furthermore, we found that p17 suppresses the formation of the TKs5/NCK1 complex. Coexpression of TKs5 and Rab40b in B16-F10 cancer cells reversed p17-modulated suppression of the formation of invadopodia. This work provides new insights into p17-modulated suppression of invadopodia formation by activating the p53/PTEN pathway, suppressing the FAK/Src pathway, and inhibiting the formation of the TKs5/NCK1 complex.
摘要：
探讨溶瘤禽呼肠孤病毒(ARV)p17蛋白是否介导细胞迁移和侵袭足形成,我们应用了几种分子生物学方法来研究相关的细胞因子和信号通路。我们发现ARVp17激活p53/磷酸酶和张力蛋白同源物（PTEN）通路，抑制粘着斑激酶（FAK）/Src信号和下游信号分子，从而抑制小鼠黑色素瘤细胞系（B16-F10）中的细胞迁移和侵袭性足病的形成。重要的是,在用突变体PTENC124A转染的细胞中，p17诱导的invadopodia形成可以逆转。发现p17蛋白显着降低酪氨酸激酶底物5（TKs5）的表达水平，Rab40b,酪氨酸激酶衔接蛋白1（NCK1）的非催化区，和基质金属蛋白酶（MMP9），表明TKs5和Rab40b被p17转录下调。此外，我们发现p17抑制了TKs5/NCK1复合物的形成。B16-F10癌细胞中TKs5和Rab40b的共表达逆转了p17调节的对侵袭性足病形成的抑制。这项工作提供了通过激活p53/PTEN通路来抑制p17调节的invadopodia形成的新见解，抑制FAK/Src通路，并抑制TKs5/NCK1复合物的形成。
