An Identity Crisis for <i>fps/fes</i>: Oncogene or Tumor Suppressor?

Sangrar, Waheed; Zirgnibl, Ralph A.; Gao, Yan; Muller, William J.; Jia, Zongchao; Greer, Peter A.

doi:10.1158/0008-5472.can-04-3468

Cited by 30 publications

(37 citation statements)

References 22 publications

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“…11 The analysis of the respective mutant proteins revealed loss-of-function mutations rather than gain-of-function. 32,33 It should be noted, however, that in these systematic searches for novel mutations, only the kinase encoding regions were sequenced and analyzed. Mutations in kinase genes also occur frequently in exons coding for regulatory regions of the protein (as in flt3).…”

Section: Activation Of Fes Kinases In Aml E Voisset Et Almentioning

confidence: 99%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

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Section: Activation Of Fes Kinases In Aml E Voisset Et Almentioning

confidence: 99%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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“…33 The mutant forms of FES appeared to have reduced kinase activity rather than being gain-of-function mutations. 34,35 To date, the function of FES in normal physiology and in pathology remains enigmatic. 34 This study was initiated to identify novel proteins required for KIT D816V signaling.…”

Section: Introductionmentioning

confidence: 99%

“…34,35 To date, the function of FES in normal physiology and in pathology remains enigmatic. 34 This study was initiated to identify novel proteins required for KIT D816V signaling. FES was found to interact with activated KIT receptor in yeast and was identified as a potentially phosphorylated protein in cells that express the KIT D816V mutant.…”

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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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“…Glutathione S-transferase fusion protein expression and purification Plasmids encoding glutathione S-transferase (GST) fusions to FES N-terminal (residues 1-459) and C-terminal (460-822) fragments of FES were previously described (29,37). The L145P and R483E mutations were generated in pGEX-FES 1-459 and pGEX-FES 460-822 plasmids using the QuikChange Site-Directed Mutagenesis Kit (Invitrogen) and verified by sequencing.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

“…In leukemias driven by oncogenic KIT receptors (e. g., D816V), FES was identified as a key effector of growth and survival signaling and a potential therapeutic target (34). Complicating this possibility are findings suggesting both tumor promoting and suppressing roles of FES, which may depend upon the tumor type and stage (24,(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

Kwok

Everingham

Zhang

et al. 2012

Molecular Cancer Research

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KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow-derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerizationdisrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosinebinding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT-and FESdependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement. Mol Cancer Res; 10(7); 881-91. Ó2012 AACR.

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An Identity Crisis for fps/fes: Oncogene or Tumor Suppressor?

Cited by 30 publications

References 22 publications

FES kinases are required for oncogenic FLT3 signaling

FES kinases are required for oncogenic FLT3 signaling

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

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

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