title: Fer protein-tyrosine kinase promotes lung adenocarcinoma cell invasion and tumor metastasis.
abstract: 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.
  
  
  CONCLUSIONS
  Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952-63. ©2013 AACR.
authors.affiliation: Division of Cancer Biology & Genetics, Queen's University, Botterell Hall, 3rd Fl, CRI315, 18 Stuart St., Kingston, ON K7L 3N6, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ahn
authors.forename: Peter
authors.initials: P
authors.lastname: Truesdell
authors.forename: Jalna
authors.initials: J
authors.lastname: Meens
authors.forename: Carli
authors.initials: C
authors.lastname: Kadish
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yang
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Boag
authors.forename: Andrew W B
authors.initials: AW
authors.lastname: Craig
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051567:Proto-Oncogene Proteins c-vav; C093651:VAV2 protein, human; C052602:proto-oncogene protein c-fes-fps; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases