The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi, Amina; Rocha, Joice; Zouanat, Fatima Z.; Hamel, Lucie; Scarlata, Eleonora; Aprikian, Armen; Chevalier, Simone

doi:10.1158/1541-7786.mcr-08-0117

Cited by 46 publications

(41 citation statements)

References 48 publications

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“…Up-regulation and activation of FER has been reported in multiple cancers, including lung (Rikova et al 2007), hepatic ), prostate (Zoubeidi et al 2009), breast (Albeck and Brugge 2011), and ovarian cancer (Ren et al 2012). Its oncogenic role has been implicated in the control of cell motility and invasion, suppression of apoptosis, and drug resistance (Greer 2002;Craig 2012).…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…Because VE-cadherin internalization is induced by its serine/threonine or tyrosine phosphorylation (10,20), and ligation of IL-6 with its receptor gp130 has been shown to activate PI3-kinase and Src kinase family member, Fer (40,42), it is possible that IL-6-induced VE-cadherin dissociation from adherens junctions may be mediated by gp130-Fer/PI3- kinase mechanism, although analysis of this mechanism was not the focus of this study. Both the IL-6-induced EC permeability and Stat3, NF-B, and p38 signaling was abolished by Jak inhibition suggesting that potential IL-6-induced activation of Src is downstream of Jak kinase.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Birukova

Tian

Meliton

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Birukova AA, Tian Y, Meliton A, Leff A, Wu T, Birukov KG. Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6. Am J Physiol Lung Cell Mol Physiol 302: L965-L975, 2012. First published February 17, 2012 doi:10.1152/ajplung.00292.2011.-Most patients with acute lung injury (ALI) and acute respiratory distress syndrome of septic and nonseptic nature require assisted ventilation with positive pressure, which at suboptimal range may further exacerbate lung dysfunction. Previous studies described enhancement of agonist-induced Rho GTPase signaling and endothelial cell (EC) permeability in EC cultures exposed to pathologically relevant cyclic stretch (CS) magnitudes. This study examined a role of pathologic CS in modulation of pulmonary EC permeability caused by IL-6, a cytokine increased in sepsis and acting in a Rho-independent manner. IL-6 increased EC permeability, which was associated with activation of Jak/signal transducers and activators of transcription, p38 MAP kinase, and NF-B signaling and was augmented by EC exposure to 18% CS. Rho kinase inhibitor Y-27632 suppressed the synergistic effect of 18% CS on IL-6-induced EC monolayer disruption but did not alter the IL-6 effects on static EC culture. 18% CS also increased IL-6-induced ICAM-1 expression by pulmonary EC and neutrophil adhesion, which was attenuated by Y-27632. Intratracheal IL-6 administration in C57BL/6J mice increased protein content and cell count in bronchoalveolar lavage fluid. These changes were augmented by high tidal volume mechanical ventilation (HTV; 30 ml/kg, 4 h). Intravenous injection of Y-27632 suppressed IL6/HTV-induced lung injury. In conclusion, this study proposes a novel mechanism contributing to two-hit model of ALI: in addition to synergistic effects on Rho-dependent endothelial hyper-permeability triggered by thrombin, TNF␣, LPS, or other agonists, ventilator-induced lung injury-relevant CS may also exacerbate Rho-independent mechanisms of EC permeability induced by other inflammatory mediators such as IL-6 via mechanisms involving Rho activity. cyclic stretch; actin; interleukin-6; vascular permeability; endothelium VENTILATOR SUPPORT IS AN INDISPENSABLE treatment for critically ill patients. However, suboptimal regimen of mechanical ventilation leading to ventilator-induced lung injury (VILI), multiorgan dysfunction, and high rates of morbidity and mortality remain one of the most important problems in the management of patients with preexisting respiratory complications in the intensive care unit (31, 34).Pathologic mechanical forces leading to VILI trigger several signaling mechanisms including activation of signaling kinases, ion channels, small GTPases, second messengers, inflammatory signaling, and gene expression (14,16,39). Increased vascular endothelial permeability (2), inflammatory cytokine production (41), and apoptosis (18) induced by pathological mechanical stimulation causes alveolar flooding, leukocyte infiltration, and hypoxemia leadi...

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“…A number of studies have identified Fer activation or upregulation in a number of different cancers, including lung (14), hepatic (15), prostate (16), and triple-negative breast cancer (17). Overexpression of Fer was also linked to quinacrine resistance and enhanced activation of NFkB pathway (5).…”

Section: Introductionmentioning

confidence: 99%

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

Ahn

Truesdell

Meens

et al. 2013

Molecular Cancer Research

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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.

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The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Cited by 46 publications

References 48 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

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Fer Protein-Tyrosine Kinase Promotes Lung Adenocarcinoma Cell Invasion and Tumor Metastasis

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