PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin-α1, a member of the leukocyte common antigen–related protein tyrosine phosphatase (LAR-RPTPs)-interacting protein family. Liprin-α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin-α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression. The compounds with the highest differential responses between high PPFIA1-expressing and silenced cells across cell lines were inhibitors targeting mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinases (ERK) signaling. KRAS proto-oncogene, GTPase (KRAS)-mutated MDA-MB-231 cells were more resistant to trametinib upon PPFIA1 knockdown compared with control cells. In contrast, liprin-α1-depleted HNSCC cells with low RAS activity showed a context-dependent response to MEK/ERK inhibitors. Importantly, we showed that liprin-α1 depletion leads to increased p-ERK1/2 levels in all our studied cell lines independent of KRAS mutational status, suggesting a role of liprin-α1 in the regulation of MAPK oncogenic signaling. Furthermore, liprin-α1 depletion led to more pronounced redistribution of RAS proteins to the cell membrane. Our data suggest that liprin-α1 is an important contributor to oncogenic RAS/MAPK signaling, and the status of liprin-α1 may assist in predicting drug responses in cancer cells in a context-dependent manner.

中文翻译：

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Liprin-α1 通过抵消 ERK 活性促进致癌 MAPK 信号传导

PTPRF 相互作用蛋白 α 1 ( PPFIA1 ) 编码 liprin-α1，它是白细胞共同抗原相关蛋白酪氨酸磷酸酶 (LAR-RPTPs) 相互作用蛋白家族的成员。Liprin-α1 定位于癌细胞周围的粘附和侵袭性结构，调节头颈鳞状细胞癌 (HNSCC) 和乳腺癌的迁移和侵袭。为了研究 liprin-α1 在抗癌药物反应中的可能作用，我们筛选了具有高内源性PPFIA1表达的细胞系中的肿瘤化合物库。在跨细胞系的高PPFIA1表达细胞和沉默细胞之间具有最高差异反应的化合物是针对丝裂原激活蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）信号传导的抑制剂。与对照细胞相比，KRAS 原癌基因 GTPase ( KRAS ) 突变的 MDA-MB-231 细胞在PPFIA1敲除后对曲美替尼 (Trametinib) 具有更强的耐药性。相比之下，具有低 RAS 活性的 liprin-α1 耗尽的 HNSCC 细胞表现出对 MEK/ERK 抑制剂的背景依赖性反应。重要的是，我们发现 liprin-α1 耗竭会导致我们研究的所有细胞系中 p-ERK1/2 水平升高，与KRAS突变状态无关，这表明 liprin-α1 在 MAPK 致癌信号传导的调节中发挥作用。此外，liprin-α1 的消耗导致 RAS 蛋白更明显地重新分布到细胞膜上。我们的数据表明，liprin-α1 是致癌 RAS/MAPK 信号传导的重要贡献者，并且 liprin-α1 的状态可能有助于以上下文依赖性方式预测癌细胞中的药物反应。