Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems

Sangrar, Waheed; Shi, Chen; Mullins, Graeme; LeBrun, David P.; Ingalls, Brian; Greer, Peter A.

doi:10.1038/onc.2014.340

Cited by 27 publications

(26 citation statements)

References 53 publications

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“…However, it has been shown that the F-BAR domain along with the F-BAR extension domain (FX) of FER could bind specifically to, and be activated by, phosphatidic acid (PA) in the plasma membrane and that this PLD-PA-mediated regulation of FER plays a positive role in cell migration (Itoh et al 2009). In addition, our published results demonstrate that ligand-induced endocytosis of RTK EGFR is suppressed in the presence of FER (Sangrar et al 2015). This suggests that FER may exert another tier of regulation on MET as well augment the kinase activity of the receptor.…”

Section: Discussionmentioning

confidence: 72%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 72%

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

et al. 2016

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“…Fps/Fes and FER are the only known members of a distinct subfamily of the non-receptor protein-tyrosine kinases. These proteins have autocatalytic properties that induce phosphorylation of their own SH-2 domains, as well as similar domains belonging to other membrane bound tyrosine kinases(13, 15, 18, 46, 47). Many studies indicate that these kinases have roles in regulating inside-out signaling that accompany receptor-ligand, cell-matrix and epithelial-immune cell interactions in the gut(42), which are probably of equal importance in lung epithelia.…”

Section: Discussionmentioning

confidence: 99%

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

et al. 2016

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Injured patients with lung contusion (LC) are at risk of developing bacterial pneumonia (PNA) followed by sepsis and death. A recent Genome-wide Association Study, showed FER gene expression positively correlating with survival rates among individuals with above conditions. We sought to determine if electroporation-mediated (EP) delivery of FER gene could indeed improve survival, in a lethal model of combined LC and PNA. C57BL/6 mice sustained unilateral LC, which preceded a 500 Klebsiella CFU inoculation by 6 hrs. In-between these insults, human FER plasmid (pFER) was introduced into the lungs followed by eight EP pulses applied externally (10ms at 200V/cm). Control groups included EP of empty vector (pcDNA3) or Na+/K+-ATPase genes (pPump) and no treatment (LC + PNA). We recorded survival, histology, lung mechanics, bronchial alveolar fluid (BAL), FER and inflammatory gene expression and bacteriology. The data shows that 7-day survival was significantly improved by pFER compared to control groups. pFER increased BAL monocytes and activated antibacterial response genes (NOS, Fizz). pFER treatment showed decreased lung and blood Klebsiella counts reaching, in some cases, complete sterilization. In conclusion, FER gene delivery promoted survival in LC+PNA mice via recruitment of activated immune cells, improving efficiency of bacterial clearance within contused lung

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“…In the resulting D743R mutant, FER and FERT proteins lack kinase activity, and the protein is unstable. Fer DR/DR mice show several defects, which implicate FER in growth factor signaling (Craig et al, 2001), hematopoiesis (Senis et al, 2003), tumorigenesis (Sangrar et al, 2015), regulation of the cytoskeleton (Sangrar et al, 2007;Xu et al, 2004) and inflammatory cell functions Khajah et al, 2013;McCafferty et al, 2002). Here, we used this murine model to evaluate the role of FER and FERT in the capacitation-associated increase of tyrosine phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm

et al. 2016

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Sperm capacitation is required for fertilization. At the molecular level, this process is associated with fast activation of protein kinase A. Downstream of this event, capacitating conditions lead to an increase in tyrosine phosphorylation. The identity of the tyrosine kinase(s) mediating this process has not been conclusively demonstrated. Recent experiments using stallion and human sperm have suggested a role for PYK2 based on the use of small molecule inhibitors directed against this kinase. However, crucially, loss-of-function experiments have not been reported. Here, we used both pharmacological inhibitors and genetically modified mice models to investigate the identity of the tyrosine kinase(s) mediating the increase in tyrosine phosphorylation in mouse sperm. Similar to stallion and human, PF431396 blocks the capacitation-associated increase in tyrosine phosphorylation. Yet, sperm from Pyk2 −/− mice displayed a normal increase in tyrosine phosphorylation, implying that PYK2 is not responsible for this phosphorylation process. Here, we show that PF431396 can also inhibit FER, a tyrosine kinase known to be present in sperm. Sperm from mice targeted with a kinase-inactivating mutation in Fer failed to undergo capacitation-associated increases in tyrosine phosphorylation. Although these mice are fertile, their sperm displayed a reduced ability to fertilize metaphase II-arrested eggs in vitro.

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Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems

Cited by 27 publications

References 53 publications

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

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

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm

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