D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites.
The c-Cbl proto-oncogene encodes a multidomain phosphoprotein that has been demonstrated to interact with a wide range of signalling proteins. The biochemical function of c-Cbl in these complexes is, however, unclear. Recent studies with the C. elegans Cbl homologue, sli-1, have suggested that Cbl proteins may act as negative regulators of EGF receptor (EGFR) signalling. As the EGFR and other protein tyrosine kinase receptor signalling pathways are highly conserved between insects and vertebrates, we sought a Drosophila homologue of c-Cbl for a detailed genetic analysis. We report here that Drosophila melanogaster has a single gene, D-cbl, that is homologous to c-cbl. We find that D-cbl encodes a 52 kDa protein that has a high degree of similarity to c-Cbl and SLI-1 across novel phosphotyrosine-binding (PTB) and RING finger domains. Surprisingly, however, D-Cbl is C-terminally truncated relative to c-Cbl and SLI-1 and consequently is unable to bind SH3-domain containing adaptor proteins, including the Drosophila Grb2 homologue, Drk. Although the D-Cbl protein lacks Drk binding sites it can nevertheless associate with a tyrosine phosphorylated protein, or is itself tyrosine phosphorylated in an DER dependent manner and associates with activated Drosophila EGF receptors (DER) in vivo. Consistent with a role for D-Cbl in DER dependent patterning in the embryo and adult, D-Cbl is expressed at a high level in early embryos and throughout the imaginal discs in third instar larvae. This study forms the basis for future genetic analysis of D-Cbl, aimed at gaining insights into the role of Cbl proteins in signal transduction.
Hime
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Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne VIC, Australia.
Dhungat
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Bowtell
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DD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018076:DNA, Complementary; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases
D018076:DNA, Complementary; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C067419:CBL protein, human; C106411:Cbl protein, Drosophila