The DFer gene of Drosophila melanogaster encodes two membrane-associated proteins that can both transform vertebrate cells

Paulson, Robert F.; Jackson, Jennie A.; Immerglück, Karin; Bishop, J. Michael

doi:10.1038/sj.onc.1200875

Cited by 27 publications

(29 citation statements)

References 28 publications

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“…FER expression has been linked to prostate cancer, with higher levels in extracts from cancers compared with normal or hyperplasic tissues (34,35). Overexpression of Drosophila FER caused malignant transformation of rodent fibroblasts (37).…”

Section: Discussionmentioning

confidence: 99%

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-κB

Guo

Stark

2011

Proc. Natl. Acad. Sci. U.S.A.

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Quinacrine, a drug with antimalarial and anticancer activities that inhibits NF-κB and activates p53, has progressed into phase II clinical trials in cancer. To further elucidate its mechanism of action and identify pathways of drug resistance, we used an unbiased method for validation-based insertional mutagenesis to isolate a quinacrine-resistant cell line in which an inserted CMV promoter drives overexpression of the FER tyrosine kinase (FER). Overexpression of FER from a cDNA confers quinacrine resistance to several different types of cancer cell lines. We show that quinacrine kills cancer cells primarily by inhibiting the activation of NF-κB and that increased activation of NF-κB through FER overexpression mediates resistance. EGF activates NF-κB and stimulates phosphorylation of FER, EGF receptor (EGFR), and ERK p42/p44, and decreased expression of FER or inhibition of ERK phosphorylation inhibits the EGF-induced activation of NF-κB. FER binds to EGFR, and overexpression of FER in cells untreated with EGF increases this association, leading to increased phosphorylation of EGFR and ERK. We conclude that FER is on a pathway connecting EGFR to NF-κB activation and that this function is responsible for FER-dependent resistance to quinacrine.

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Section: Discussionmentioning

confidence: 99%

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-κB

Guo

Stark

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…One way in which functional analogies between vertebrate proto-oncogenes and their counterparts in Drosophila have been demonstrated is to show that Drosophila homologs or chimeras of Drosophila and vertebrate oncogenes transform vertebrate cells in culture (Schejter and Shilo, 1985;Holland et al, 1990;Egan et al, 1993;Ramakrishna and Brown, 1993;Paulson et al, 1997). We have taken the opposite approach to explore functional analogies between Drosophila abl and human bcr-abl using¯ies expressing human/¯y chimeric bcr-abl oncogenes.…”

Section: Introductionmentioning

confidence: 99%

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

Petersen

et al. 1999

Oncogene

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We targeted expression of human/¯y chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/¯y chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant¯ies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality. Expression of P210 or P185 in the eye imaginal disc produced a dominant rough eye phenotype that was dependent on dosage of the transgene. Drosophila Enabled, previously identi®ed as a suppressor of the abl mutant phenotype and substrate for Drosophila Abl kinase, had markedly increased phosphotyrosine levels in Bcr-Abl expressing Drosophila, indicating that it is a substrate for Bcr-Abl as well. Drosophila, therefore, is a suitable model system to identify Bcr-Abl interactions important for signal transduction and oncogenesis.

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“…Fer kinase is ubiquitously expressed (17) and localizes to the nucleus in a cellcycle-dependent manner (18). Forced expression of Fer can transform cells in culture (19) and altered levels of Fer are associated with proliferation of prostate cells (20). We showed in previous studies that, as with their mammalian orthologs, C. elegans FRK-1 and HMP-2 β-catenin interact in vitro (15).…”

Section: Hmp-2 Relocalizes To the Nucleus In The Absence Of The Frk-1mentioning

confidence: 99%

Repression of Wnt signaling by a Fer-type nonreceptor tyrosine kinase

Putzke

Rothman

2010

Proc. Natl. Acad. Sci. U.S.A.

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The Wnt signaling pathway must be properly modulated to ensure an appropriate output: pathological conditions result from either insufficient or excessive levels of Wnt signal. For example, hyperactivation of the Wnt pathway is associated with various cancers and subnormal Wnt signaling can lead to increased invasiveness of tumor cells. We found that the Caenorhabditis elegans ortholog of the Fer nonreceptor tyrosine kinase, FRK-1, limits Wnt signaling by preventing the adhesion complex-associated β-catenin, HMP-2, from participating in Wnt-dependent specification of the endoderm during embryogenesis. Removal of FRK-1 function results in relocalization of HMP-2 to the nucleus of epidermal cells, and allows it to substitute for WRM-1, the nuclear β-catenin that normally transduces the Wnt signal during endoderm development. APR-1, the C. elegans APC ortholog, is similarly required to prevent HMP-2 relocalization and keeps it from participating in Wnt signal transduction; this finding partially explains the paradoxical observation that APR-1 acts either negatively or positively in Wnt signaling, depending on context. The apparent hyperactivation of the Wnt response in the absence of FRK-1 leads to hyperproliferation in the endoderm, as is also seen when WRM-1 is overexpressed in wild-type embryos. The specification and proliferation activities of Wnt signaling are separable: although the Tcf/Lef factor POP-1 acts in Wnt-dependent endoderm specification, it is not apparently required for hyperproliferation resulting from excessive Wnt signaling. These findings highlight a role for a Fer-type kinase in setting the proper levels of Wnt signaling and demonstrate the importance of this modulation in ensuring appropriate cell division.

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The DFer gene of Drosophila melanogaster encodes two membrane-associated proteins that can both transform vertebrate cells

Cited by 27 publications

References 28 publications

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-κB

FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-κB

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

Repression of Wnt signaling by a Fer-type nonreceptor tyrosine kinase

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