Hannah Robertson

Rocks of ages

Summary A series of rock paintings in Arnhem Land reveal one of the longest records of human illustration and surprises about native Australian history. Hannah Robertson reports.

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 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 co-operate 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.

The Drosophila STIM1 orthologue, dSTIM, has roles in cell fate specification and tissue patterning.

BackgroundMammalian STIM1 and STIM2 and the single Drosophila homologue dSTIM have been identified as key regulators of store-operated Ca2+ entry in cells. STIM proteins function both as molecular sensors of Ca2+concentration in the endoplasmic reticulum (ER) and the molecular triggers that activate SOC channels in the plasma membrane. Ca2+ is a crucial intracellular messenger utilised in many cellular processes, and regulators of Ca2+ homeostasis in the ER and cytosol are likely to play important roles in developmental processes. STIM protein expression is altered in several tumour types but the role of these proteins in developmental signalling pathways has not been thoroughly examined.ResultsWe have investigated the expression and developmental function of dSTIM in Drosophila and shown that dSTIM is widely expressed in embryonic and larval tissues. Using the UAS-Gal4 induction system, we have expressed full-length dSTIM protein and a dsRNAi construct in different tissues. We demonstrate an essential role for dSTIM in larval development and survival, and a tissue-specific role in specification of mechanosensory bristles in the notum and specification of wing vein thickness.ConclusionOur studies show that dSTIM regulates growth and patterning of imaginal discs and indicate potential interactions with the Notch and Wingless signaling pathways. These interactions may be relevant to studies implicating STIM family proteins in tumorigenesis.

Dynamic expression of alternate splice forms of D-cbl during embryogenesis.

The Cbl family of proteins act as E3 ubiquitin-protein ligases and have been associated with the down regulation of a variety of receptor tyrosine kinases. Cbl proteins associate with many different cell signalling molecules suggesting that they may have functions outside of the RING finger-mediated ubiquitin ligase activity. The Drosophila melanogaster cbl gene (D-cbl) encodes two splice forms (Oncogene 19 (2000) 3299). Here we report on the differential expression of these isoforms during Drosophila embryogenesis. Both isoforms are maternally expressed but the long isoform of D-cbl is also transiently expressed in the invaginating mesoderm and later is specifically expressed in neurons of the central nervous system (CNS). Cbl protein is shown to be localised to axons of the longitudinal connectives and commissures in the central nervous system.

Akap200 suppresses the effects of Dv-cbl expression in the Drosophila eye.

The Drosophilamelanogaster orthologue of the c-Cbl proto-oncogene acts to downregulate signalling from receptor tyrosine kinases by enhancing endocytosis of activated receptors. Expression of an analogue of the C-terminally truncated v-Cbl oncogene, Dv-cbl, in the developing Drosophila eye conversely leads to excess signalling and disruption to the well-ordered adult compound eye. Co-expression of activated Ras with Dv-cbl leads to a severe disruption of eye development. We have used a transposon-based inducible expression system to screen for molecules that can suppress the Dv-cbl phenotype and have identified an allele that upregulates the A-kinase anchoring protein, Akap200. Overexpression of Akap200 not only suppresses the phenotype caused by Dv-cbl expression, but also the severe disruption to eye development caused by the combined expression of Dv-cbl and activated Ras. Akap200 is also endogenously expressed in the developing Drosophila eye at a level that modulates the effects of excessive signalling caused by expression of Dv-cbl.