Fer protein-tyrosine kinase promotes lung adenocarcinoma cell invasion and tumor metastasis.

Abstract

UNLABELLED:

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.

IMPLICATIONS:

Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952-63. ©2013 AACR.

• Authors: Joseph Ahn, Peter Truesdell, Jalna Meens, Carli Kadish, Xiaolong Yang, Alexander H Boag, Andrew W B Craig
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 8 Pg. 952-63 (Aug 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23699534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Proto-Oncogene Proteins c-vav
• VAV2 protein, human
• proto-oncogene protein c-fes-fps
• ErbB Receptors
• Protein-Tyrosine Kinases

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• ErbB Receptors (metabolism)
• Humans
• Lung (enzymology)
• Lung Neoplasms (enzymology, genetics, pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phosphorylation
• Protein-Tyrosine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-vav (genetics, metabolism)
• Signal Transduction