title: HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer.
abstract: 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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Fan
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA;
authors.forename: Siwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Tonks
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor; D006801:Humans; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; C052602:proto-oncogene protein c-fes-fps; D017228:Hepatocyte Growth Factor; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met
keywords: FER; GAB1; MET; ovarian cancer; tyrosine phosphorylation