The Fes tyrosine kinase: a signal transducer that regulates myeloid-specific gene expression through transcriptional activation

Kim, Juyong Brian; Ogata, Yoshiyasu; Ali, Humayra; Feldman, Ricardo A.

doi:10.1016/j.bcmd.2003.12.004

Cited by 8 publications

(9 citation statements)

References 36 publications

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“…Using a soft-agar colony-forming assay for anchorage-independent growth, we first tested the ability of TAE684 to inhibit Rat-2 transformation by two different active forms of c-Fes. Rat-2 cells expressing GFP fusions of c-Fes-L145P or an active c-Fes/v-Fps chimera (Kim et al, 2004) were grown in soft-agar in the presence of various inhibitor concentrations and the number of transformed colonies were counted two weeks later. As shown in Figure 5, TAE684 potently inhibited soft-agar colony formation by Rat-2 cells expressing either of the transforming variants of c-Fes by more than 50% at 100 nM.…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Hellwig

Miduturu

Kanda

et al. 2012

Chemistry & Biology

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SUMMARY The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here we report the identification of Type I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor, TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a novel role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase.

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Section: Resultsmentioning

confidence: 99%

Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Hellwig

Miduturu

Kanda

et al. 2012

Chemistry & Biology

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“…Overexpression of normal c-Fes or activated forms induces differentiation of myeloid leukemia cell lines K562 (Yu et al, 1989), U937 (Kim and Feldman, 2002), and 32D (Kim et al, 2003). Transcription factors that are essential for myeloid cell differentiation are activated by cFes (Borellini et al, 1991;Kim et al, 2004). c-Fes is activated downstream of hematopoietic growth factors and cytokines, including G-CSF (Hanazono et al, 1993a;Brizzi et al, 1996;Park et al, 1998), erythropoietin (Hanazono et al, 1993b), IL-6 (Matsuda et al, 1995), and IL-4 (Izuhara et al, 1994).…”

Section: Introductionmentioning

confidence: 98%

Spatial and Temporal Changes in the Subcellular Localization of the Nuclear Protein–Tyrosine Kinase, c-Fes

Carlson

Yates

Slamon³

et al. 2005

DNA and Cell Biology

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Tyrosine phosphorylation has emerged as a mechanism to control cellular events in the nucleus. The c-Fes protein-tyrosine kinase is an important regulator of cell growth and differentiation in several cell types, and is found in the nucleus of hematopoietic cells. In this study, we showed nuclear localization of c-Fes in both hematopoietic (K562, TF-1, HEL, U937, and HL-60) and nonhematopoietic cell lines (293T, CaOv3, TfxH, MG-63, HeLa, DU-145) by immunofluorescence and confocal microscopy. c-Fes showed striking changes in subcellular localization at specific stages of mitosis. In interphase cells, the intranuclear distribution of c-Fes was diffuse with occasional bright foci. Some c-Fes was present in the cytosol after breakdown of the nuclear membrane, in prometaphase. At prometaphase and metaphase c-Fes was also associated with the chromosomes, in a punctate pattern that partially overlapped with the centromere. Further comparison with proteins that are known components of the kinetochore suggested that some c-Fes protein was located at the centromeric alpha-satellite DNA, between the kinetochores. At anaphase and telophase, c-Fes was entirely cytoplasmic and no protein was found associated with the chromosomes. The timing of c-Fes' appearance at the centromere coincides with the period of kinetochore assembly. These data suggest that c-Fes is recruited to the kinetochore during mitosis.

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“…In vitro, differentiation of the myeloid leukemia progenitor cell line, HL-60, into the granulocyte (Manfredini et al, 1993) or macrophage lineages (Manfredini et al, 1997) is blocked when c-fes expression is inhibited by antisense oligonucleotides. Expression of a chimeric, activated c-Fes kinase induces terminal differentiation of macrophage (Kim and Feldman, 2002;Kim et al, 2004) and granulocyte progenitors (Kim et al, 2003). Results from transgenic mice are less straightforward.…”

Section: Discussionmentioning

confidence: 97%

“…Numerous studies of perturbed c-Fes expression, however, point towards a role in regulating myeloid cell differentiation (Hackenmiller and Simon, 2002;Sangrar et al, 2003;Senis et al, 2003) and function (Senis et al, 1999;Hackenmiller et al, 2000). Recently, it was discovered that activation of c-Fes kinase leads to phosphorylation of transcription factors that are essential for myeloid cell differentiation (Kim et al, 2004). It is not known whether c-Fes phosphorylates these factors directly.…”

Section: Discussionmentioning

confidence: 98%

Expression of c-Fes Protein Isoforms Correlates with Differentiation in Myeloid Leukemias

Carlson¹,

McAdara²,

Browning³

et al. 2005

DNA and Cell Biology

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The cellular fes gene encodes a 93-kilodalton protein-tyrosine kinase (p93) that is expressed in both normal and neoplastic myeloid cells. Increased c-Fes expression is associated with differentiation in normal myeloid cells and cell lines. Our hypothesis was that primary leukemia cells would show a similar pattern of increased expression in more differentiated cells. Therefore, we compared c-Fes expression in cells with an undifferentiated, blast phenotype (acute myelogenous leukemia--AML) to cells with a differentiated phenotype (chronic myelogenous leukemia--CML). Instead of differences in p93 expression levels, we found complex patterns of c-Fes immunoreactive proteins that corresponded with differentiation in normal and leukemic myeloid cells. The "blast" pattern consisted of c-Fes immunoreactive proteins p93, p74, and p70; the "differentiated" pattern showed two additional c-Fes immunoreactive proteins, p67 and p62. Using mRNA from mouse and human cell lines, we found deletion of one or more exons in the c-fes mRNA. Those deletions predicted truncation of conserved domains (CDC15/FCH and SH2) involved in protein-protein interactions. No deletions were found, however, within the kinase domain. We infer that alternative splicing generates a family of c-Fes proteins. This may be a mechanism to direct the c-Fes kinase domain to different subcellular locations and/or substrates at specific stages of myeloid cell differentiation.

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The Fes tyrosine kinase: a signal transducer that regulates myeloid-specific gene expression through transcriptional activation

Cited by 8 publications

References 36 publications

Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase

Spatial and Temporal Changes in the Subcellular Localization of the Nuclear Protein–Tyrosine Kinase, c-Fes

Expression of c-Fes Protein Isoforms Correlates with Differentiation in Myeloid Leukemias

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