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A Drosophila analogue of v-Cbl is a dominant-negative oncoprotein in vivo
H Robertson1, G R Hime, H Lada
1Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, VIC, Australia.
Abstract:
Cells rely on the ability to receive and interpret external signals to regulate growth, differentiation, and death. Positive transduction of these signals to the cytoplasm and nucleus has been extensively characterized, and genetic studies in Drosophila have made major contributions to the understanding of these pathways. Less well understood, but equally important, are the mechanisms underlying signal down-regulation. Here we report biochemical and genetic characterization of the Drosophila homologue of c-Cbl, a negative regulator of signal transduction with ubiquitin-protein ligase activity. A new isoform of D-Cbl, D-CblL, has been identified that contains SH3-binding and UBA domains previously reported to be absent. Genetic analysis demonstrates that Dv-cbl, analogous to the mammalian v-cbl oncogene, is a dominant negative mutation able to enhance signalling from the Drosophila Egfr and cooperate with activating mutations in the sevenless pathway to produce melanotic tumours. In addition, our data show genetic and biochemical links between D-Cbl and proteins involved in endocytosis and ubiquitination, suggesting that v-Cbl may exert its oncogenic effect by enhancing receptor signalling as a consequence of suppressing receptor endocytosis.
Insights
Researchers characterized Drosophila c-Cbl (D-Cbl), a negative regulator of signal transduction. They identified a new isoform, D-CblL, and found Dv-cbl mutations enhance signaling, leading to tumor formation by suppressing receptor endocytosis.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Genetics
Background:
- Cellular processes like growth, differentiation, and death depend on signal reception and interpretation.
- While signal transduction is well-studied, mechanisms of signal down-regulation are less understood.
- Drosophila genetics has significantly advanced understanding of signal transduction pathways.
Purpose of the Study:
- To biochemically and genetically characterize the Drosophila homologue of c-Cbl (D-Cbl), a negative regulator of signal transduction.
- To investigate the function of a newly identified D-Cbl isoform, D-CblL.
- To analyze the role of Dv-cbl mutations in Drosophila signaling pathways and oncogenesis.
Main Methods:
- Biochemical characterization of D-Cbl and its isoforms.
- Genetic analysis of Dv-cbl mutations in Drosophila.
- Investigating interactions between D-Cbl, endocytosis, and ubiquitination pathways.
Main Results:
- A novel D-Cbl isoform, D-CblL, containing previously absent domains was identified.
- Dv-cbl acts as a dominant negative mutation, enhancing Drosophila Egfr signaling.
- Dv-cbl cooperates with sevenless pathway mutations to induce melanotic tumors.
- Genetic and biochemical links between D-Cbl and endocytosis/ubiquitination proteins were established.
Conclusions:
- D-Cbl plays a crucial role in negative regulation of signal transduction in Drosophila.
- The oncogenic effect of v-Cbl may stem from enhanced receptor signaling due to suppressed receptor endocytosis.
- D-Cbl's involvement in endocytosis and ubiquitination highlights its complex role in signal regulation.
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