HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

• Published in: Genes & development Vol. 30; no. 13; pp. 1542 - 1557
• Main Authors: Fan, Gaofeng, Zhang, Siwei, Gao, Yan, Greer, Peter A., Tonks, Nicholas K.
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.07.2016
• Subjects: Animals; Cell Line, Tumor; Cell Movement; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Mice, SCID; Neoplasm Invasiveness - genetics; Neoplasm Metastasis; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Ovarian Neoplasms - physiopathology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Research Paper; Signal Transduction - genetics; Tumor Cells, Cultured; GAB1; FER; tyrosine phosphorylation; ovarian cancer; MET
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.284166.116

Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2–ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer.