酪氨酸磷酸酶在卵巢癌细胞 HER2 定向运动中的作用：涉及 PTPN12、ERK5 和 FAK。
Tyrosine phosphatases in the HER2-directed motility of ovarian cancer cells: Involvement of PTPN12, ERK5 and FAK.
机构信息
Department of Experimental Pathology, via Roma 55, University of Pisa, 56126 Pisa, Italy.
出版信息
Anal Cell Pathol (Amst). 2011;34(3):101-12. doi: 10.3233/ACP-2011-0008.
BACKGROUND
HER2 activation in tumours supports multiple signalling pathways, including those regulating invasion and metastasis. Among the involved genes, tyrosine and dual specificity phosphatases (PTPs and DSPs) may play a relevant, though not completely clear role.
METHODS
HER2 was silenced in ovarian SKOV-3 cells, a genome-wide expression analysis of PTPs and DSPs was performed, the effects on cell motility were analysed and compared with those of PTPN12-silencing, focusing on FAK.
RESULTS
HER2-silencing altered the expression of 4 PTPs and 6 DSPs; PTPN12 displayed also 3-4-fold protein increase. Conversely, PTPN12-silencing enhanced migration, suggesting that PTPN12 down-modulation by HER2 favours motility. HER2-silencing inactivated FAK, in quiescent and migrating cells, involving FAK dephosphorylation at Y397 and S910. Conversely, in PTPN12-silenced cells FAK activity was close to control, altogether suggesting that PTPN12 targets Y397. As regards to S910, cell-treatment with the MEK inhibitor UO126 and ERK5-silencing indicated its targeting by ERK5. Loss of pS910 and decreased ERK5 kinase activity in HER2-silenced cells confirmed their control by HER2.
CONCLUSIONS
The results indicate the contribution of PTPN12, targeting FAK Y397, and ERK5, targeting FAK S910, to the HER2-driven cell motility, thus depicting new aspects of the complex cross-talk between HER2 and the motility machinery.
背景
肿瘤中 HER2 的激活支持多种信号通路，包括调节侵袭和转移的信号通路。在涉及的基因中，酪氨酸和双特异性磷酸酶（PTPs 和 DSPs）可能发挥相关但不完全清楚的作用。
方法
沉默卵巢 SKOV-3 细胞中的 HER2，进行 PTPs 和 DSPs 的全基因组表达分析，分析细胞迁移的影响，并与 PTPN12 沉默进行比较，重点关注 FAK。
结果
HER2 沉默改变了 4 个 PTPs 和 6 个 DSPs 的表达；PTPN12 也显示出 3-4 倍的蛋白增加。相反，PTPN12 沉默增强了迁移，表明 HER2 下调 PTPN12 有利于迁移。HER2 沉默在静止和迁移细胞中使 FAK 失活，涉及 FAK 在 Y397 和 S910 处去磷酸化。相反，在 PTPN12 沉默的细胞中，FAK 活性接近对照，这表明 PTPN12 靶向 Y397。至于 S910，细胞用 MEK 抑制剂 UO126 和 ERK5 沉默处理表明其由 ERK5 靶向。在 HER2 沉默的细胞中失去 pS910 和降低 ERK5 激酶活性证实了它们由 HER2 控制。
结论
结果表明 PTPN12 靶向 FAK Y397 和 ERK5 靶向 FAK S910 对 HER2 驱动的细胞迁移有贡献，从而描绘了 HER2 与运动机制之间复杂的串扰的新方面。
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