Regulation of Drosophila Jun by phosphorylation and the ubiquitin system during eye development

Abstract: The goal of these studies has been to elucidate the biological relevance of post-translational modifications in the context of a living organism. The model system used is photoreceptor differentiation during development of the compound eye in the fruit fly Drosophila melanogaster. Important signal transduction pathways in this process consist of receptor tyrosine kinases (RTKs) coupled to a mitogen activated protein kinase cascade. In the nucleus several transcription factors have been implicated as mediators of the pathway. The first part of the work presented here focuses on the role of signal-dependent phosporylation of D-Jun in photoreceptor differentiation. It appears that Rolled is the only kinase phosphorylating D-Jun during eye development. Interestingly, Rolled is a kinase of the extracellular signal reulated (ERK) sub-type of kinases, in contrast to the c-Jun N-terminal kiases (JNKs), which phosphorylate c-Jun in many cell culture systems. Phosphorylation by Rolled appears to be important for D-Jun function, since a D-Jun protein with the phosphorylation sites mutated to the non-phosphorylatable amino acid alanine can suppress formation of ectopic photoreceptors. Another study addresses the role of ubiquitin- dependent proteolysis in photoreceptor differentiation. A loss-of-function mutation in a gene involved in ubuquitin-dependent proteolysis (fat facets) causes a zygotic phenotype with 1-2 ectopic photoreceptors per unit eye. Genetic interactions with components of the neurogenic signal transduction pathway suggest that the pathway is hyperactivated in the faf mutants. This idea is consistent with the observed increased level and prolonged expression of D-Jun protein in faf eye imaginal discs. Since reducing D-Jun activity suppresses the formation of ectopic photoreceptors caused by faf, it is likely that the increased expression of D-Jun contributes to the phenotype.