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 kinaseindependent 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.

Spatial regulation of signaling by the coordinated action of the protein tyrosine kinases MET and FER

“…Our previous work established a novel ligand- and autophosphorylation-independent activation of MET, the hepatocyte growth factor receptor (HGFR), by the non-receptor PTK FER [7]. To define further this mechanism of activation, we examined the tyrosine phosphorylation of MET/HGFR that was promoted by FER following overexpression in HEK 293T cells.…”

“…This illustrates a new aspect of the control of HGFR/MET function. It is interesting to note that both up-regulation of FER and down-regulation of PTP1B (Fig 7) has been detected in ovarian carcinoma-derived cell lines [7]. Therefore, one would anticipate that this mechanism may underlie persistent activation of HGF-MET signaling in this disease, and perhaps may present new opportunities for therapeutic intervention.…”

“…This tyrosine phosphorylation creates docking sites for recruiting SH2 or PH domain-containing adaptor proteins, such as GRB2, GAB1 and SHC, and assembles downstream signaling components to activate RAS–MAPK, PI3K–AKT, and STAT3 signaling pathways [5, 6]. Recently, we identified an alternative, HGF-independent pathway for activation of MET, through a non-receptor protein tyrosine kinase (PTK), the feline sarcoma-related kinase FER [7]. We demonstrated that FER could phosphorylate Tyr1349 of MET directly and promote a kinase-independent scaffolding function of the receptor.…”

“…We demonstrated that FER could phosphorylate Tyr1349 of MET directly and promote a kinase-independent scaffolding function of the receptor. This led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2–ERK signaling pathway in an ovarian cancer cell setting [7]. Overexpression of MET is a feature of several cancer cells [6, 8, 9].…”

MAN2A1–FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice

“…Several studies showed that FER activates androgen receptor ( AR ) by phosphorylating Tyr223 in AR 23 . Some studies indicate that FER is an essential component of stem cell tyrosine kinase 1 ( STK1 ) 24 and mast cell growth factor receptor ( kit ) 25, 26 and c-met 27 signaling. Over-expression of FER is associated with poor clinical outcomes of breast cancer 28 , renal cell carcinoma 29, 30 , non-small cell lung cancer 31, 32 and hepatocellular carcinoma 33 .…”