Division of Cancer Biology & Genetics, Queen's University, Botterell Hall, 3rd Fl, CRI315, 18 Stuart St., Kingston, ON K7L 3N6, Canada.
Mol Cancer Res. 2013 Aug;11(8):952-63. doi: 10.1158/1541-7786.MCR-13-0003-T. Epub 2013 May 22.
Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non-small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis.
Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952-63. ©2013 AACR.
表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）中经常扩增或突变。尽管 Fer 蛋白酪氨酸激酶信号在 EGFR 的下游，但它在 NSCLC 肿瘤进展中的作用尚未报道。在这里，与正常肺上皮相比，Fer 激酶在 NSCLC 肿瘤中升高。NSCLC 细胞中的 EGFR 信号促进 Fer 的快速激活和向片状伪足的增加定位。与对照细胞相比，在 H1299 肺腺癌细胞（Fer KD）中稳定沉默 Fer 导致 EGFR 诱导的片状伪足形成受损。Fer KD NSCLC 细胞显示出 Vav2 酪氨酸磷酸化减少，这与 Fer 介导的 Vav2 酪氨酸-172 上的直接磷酸化相关，这先前被报道增加了 Vav2 的鸟嘌呤核苷酸交换因子活性。事实上，Fer KD 细胞在 Rac-GTP 向片状伪足、细胞迁移和体外细胞侵袭中的定位存在缺陷。为了测试 Fer 在 NSCLC 进展和转移中的作用，对照和 Fer KD 细胞在小鼠中作为皮下肿瘤生长。尽管 Fer 对于肿瘤生长不是必需的，但 Fer KD 肿瘤荷瘤小鼠自发转移的数量明显减少。综合这些数据表明，Fer 蛋白酪氨酸激酶在 NSCLC 肿瘤中升高，对于细胞侵袭和转移很重要。
Fer 蛋白酪氨酸激酶是转移性肺癌的潜在治疗靶点。Mol Cancer Res; 11(8); 952-63. ©2013 AACR.
