Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival

Sangrar, Waheed; Gao, Yan; Bates, Barbara; Zirngibl, Ralph A; Greer, Peter A.

doi:10.1016/j.exphem.2004.07.004

Cited by 13 publications

(9 citation statements)

References 56 publications

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“…Using a kinase deficient transgenic model, significant but nonlethal intestinal epithelial disruption and exaggerated neutrophilia were found after insult (42, 45, 48, 49). Other authors have observed that members of this family are important in myeloid cell recruitment and differentiation (14, 41, 49). …”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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

et al. 2016

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“…[2][3][4] Expression of fps has been described in haematopoietic cells including monocytes/macrophages, neutrophils, mast cells, platelets and erythrocytes; as well as in some neuronal, epithelial and vascular endothelial cells. In contrast, during development, fps is expressed in all three germ layers [5][6][7] (reviewed in ref. 8).…”

Section: Introductionmentioning

confidence: 99%

The Fps/Fes kinase regulates leucocyte recruitment and extravasation during inflammation

et al. 2007

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SummaryFps/Fes and Fer comprise a distinct subfamily of cytoplasmic proteintyrosine kinases, and have both been implicated in the regulation of innate immunity. Previous studies showed that Fps/Fes-knockout mice were hypersensitive to systemic lipopolysaccharide (LPS) challenge, and Fer-deficient mice displayed enhanced recruitment of leucocytes in response to localized LPS challenge. We show here for the first time, a role for Fps in the regulation of leucocyte recruitment to areas of inflammation. Using the cremaster muscle intravital microscopy model, we observed increased leucocyte adherence to venules, and increased rates and degrees of transendothelial migration in Fps/Fes-knockout mice relative to wild-type animals subsequent to localized LPS challenge. There was also a decreased vessel wall shear rate in the post-capillary venules of LPS-challenged Fps/Fes-knockout mice, and an increase in neutrophil migration into the peritoneal cavity subsequent to thioglycollate challenge. Using flow cytometry to quantify the expression of surface molecules, we observed prolonged expression of the selectin ligand PSGL-1 on peripheral blood neutrophils from Fps/Fes-knockout mice stimulated ex vivo with LPS. These observations provide important insights into the observed in vivo behaviour of leucocytes in LPS-challenged Fps/Fes-knockout mice and provide evidence that the Fps/Fes kinase plays an important role in the innate immune response.

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“…[17][18][19][20]47 In primary erythroid cells, the activation of FES and/or FER downstream of wild-type KIT receptor has been suggested using a dual-specific antibody. 25 Another study showed increased FER phosphorylation in response to SCF in BMMCs. 48 The function of FER in KIT-mediated adhesion and chemotaxis was suggested through the use of a dominant-negative mutant protein.…”

Section: Fes Fer and Cell-surface Receptorsmentioning

confidence: 99%

“…26 Several mouse models of FES have been generated with either a null allele, 23,27 a knock-in of an inactive kinase, 22,28 a truncated FES protein, 29 or transgenic mice expressing an active form of FES. 25,30,31 They all showed a role for FES, albeit nonessential, in the homeostasis of the myeloid cell compartment, and a role in innate immunity has been highlighted in the knock-out mice. 23,27,32 Mutations of FES have been recently reported in colorectal cancers.…”

Section: Introductionmentioning

confidence: 99%

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

Voisset

Lopez

Dubreuil

et al. 2007

Blood

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KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KIT D816V . FES is phosphorylated on tyrosine residues in cells that carry KIT D816V mutation, and this phosphorylation is KIT dependent. Reduction of FES expression using RNA interference results in decreased cell proliferation in human or murine cells harboring KIT D816V IntroductionThe proto-oncogene c-kit encodes a receptor with tyrosine kinase activity which is essential for hematopoiesis and the development of melanoblasts, germ cells, and interstitial cells of Cajal. Gain-offunction mutations of KIT are implicated in human pathologies. These mutations have been classified as regulatory-type mutations when they affect domains of the receptor necessary for maintaining KIT autoinhibition and structural-type mutations when they directly affect the catalytic domain. Juxtamembrane mutations of KIT are commonly found in gastrointestinal stromal tumors (GISTs), 1 whereas kinase domain mutations are mainly found in mastocytosis, 2 hematologic neoplasms, [3][4][5] and germ-cell tumors. [6][7][8] Very recently, both juxtamembrane and kinase domain mutations of KIT have also been reported in melanomas. 9 The most frequent mutation affects codon 816 in human c-kit cDNA, which corresponds to codon 814 in the homologous mouse sequence. 10 Whereas tyrosine kinase inhibitors such as imatinib are very efficient on wild-type KIT (KIT WT ) and KIT juxtamembrane mutations, KIT D816V is resistant to this treatment. [11][12][13] Therefore, drugs that could target this mutant or an essential downstream effector would be useful tools for the study and the treatment of the associated diseases.Signaling proteins activated downstream of gain-of-function mutants of KIT include many proteins shown previously to participate in wild-type KIT receptor signal transduction. 14,15 They include the classical phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways, as well as a number of signaling proteins activated by many cell-surface receptors such as p38, JNK, VAV, STAT-1, STAT-3, and STAT-5. Activation of PI3K is critical for both WT and mutant KIT in all models studied, while the activation of the mitogen-activated protein (MAP) kinases ERK-1 and ERK-2 appears to be dependent on the cellular context. The importance of each protein or signaling pathway activated downstream of KIT D816V has yet to be fully evaluated.Fps/fes was originally identified as an oncogene from avian (fps) and feline (fes) retroviruses. FES (feline sarcoma) and FER (FES-related) proteins are the only 2 members of a subfamily of cytoplasmic protein tyrosine kinase. 16 FES has been shown to associate with growth factor an...

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Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival

Cited by 13 publications

References 56 publications

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

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

The Fps/Fes kinase regulates leucocyte recruitment and extravasation during inflammation

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

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