A Drosophila analogue of v-Cbl is a dominant-negative oncoprotein in vivo

Cells rely on the ability to receive and interpret external signals to regu late growth, differentiation, and death. Positive transduction of these sig nals to the cytoplasm and nucleus has been extensively characterized, and g enetic studies in Drosophila have made major contributions to the understan ding of these pathways, Less well understood, but equally important, are th e mechanisms underlying signal down-regulation. Here me report biochemical and genetic characterization of the Drosophila homologue of c-Cbl, a negati ve regulator of signal transduction with ubiquitin-protein ligase activity. A new isoform of D-Cbl, D-CblL, has been identified that contains SH3-bind ing and UBA domains previously reported to he absent. Genetic analysis demo nstrates that Dv-cbl, analogous to the mammalian v-cbl oncogene, is a domin ant negative mutation able to enhance signalling from the Drosophila Egfr a nd 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, sug gesting that v-Cbl may exert its oncogenic effect by enhancing receptor sig nalling as a consequence of suppressing receptor endocytosis.