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

Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Cancer Research (Impact Factor: 9.33). 06/2005; 65(9):3518-22. DOI: 10.1158/0008-5472.CAN-04-3468
Source: PubMed


Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.

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Available from: Waheed Sangrar, Oct 07, 2014
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    • "Expression of c-Fes is readily detected in normal colonic epithelium, but is frequently absent in matched tumor samples as well as in human colorectal cancer cell lines as a result of extensive promoter methylation (Delfino et al., 2006; Shaffer and Smithgall, 2009). In a mouse model of breast cancer, tumor onset was accelerated in homozygous-null c-fes mice, and this effect was rescued by a c-fes transgene (Sangrar et al., 2005). Taken together, these data point to a tumor suppressor function for c-Fes in some epithelial cancers. "
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    ABSTRACT: The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here, we report the identification of types 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 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.
    Chemistry & biology 04/2012; 19(4):529-40. DOI:10.1016/j.chembiol.2012.01.020 · 6.65 Impact Factor
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    • "Although FES has been historically viewed as a proto-oncogene because of its proteintyrosine kinase activity, several recent reports have established a tumor suppressor function for FES in epithelial cancers (Sangrar et al., 2005; Delfino et al., 2006b). Greer and colleagues determined that null or kinase-inactivating FES mutations accelerated tumor onset in a mouse breast epithelial cancer model system (Sangrar et al., 2005). Importantly, the kinetics of tumor onset in targeted FES null mice was restored with a FES transgene in this study, allowing direct attribution of the effect on tumor latency to FES gene loss. "
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    ABSTRACT: The FES locus encodes a unique nonreceptor protein-tyrosine kinase (FES) traditionally viewed as a proto-oncogene but more recently implicated as a tumor suppressor in colorectal cancer (CRC). Recent studies have demonstrated that while FES is expressed in normal colonic epithelium, expression is lost in tumor tissue and colorectal cancer cell lines, a finding common among tumor suppressors. Here we provide compelling evidence that promoter methylation is an important mechanism responsible for downregulation of FES gene expression in colorectal cancer cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in the expression of functional FES transcripts in all CRC cell lines examined, including Caco-2, COLO 320, DLD-1, HCT 116, SNU-1040, SW-480, and HT-29. Bisulfite sequencing of genomic DNA isolated from 5-aza-2'-deoxycytidine-treated HT-29 cells identified methylated CpG dinucleotides immediately upstream from the FES transcription initiation sites. In contrast, this region of the FES promoter was hypomethylated in genomic DNA from normal colonic epithelium. In addition, methylation completely blocked the activity of the FES promoter in reporter gene assays. Promoter methylation is a previously unrecognized mechanism by which FES expression is suppressed in CRC cell lines, and is consistent with a tumor suppressor role for FES in this tumor site despite its tyrosine kinase activity.
    Genes Chromosomes and Cancer 03/2009; 48(3):272-84. DOI:10.1002/gcc.20638 · 4.04 Impact Factor
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