Regulation of ERK and $NF-\kappa B$ pathways in drosophila development

Abstract

The Ras/extracellular signal-regulated kinase (ERK) and the NF-kB signaling pathways are critically involved in diverse biological processes, including mitogenesis, cellular differentiation, and immune reactions. 1) Using gain-of-function and null mutants of RSK, its physiological role was characterized in Drosophila. Surprisingly, RSK-null mutants were viable, but exhibited developmental abnormalities related to an enhanced ERK-dependent cellular differentiation such as ectopic photoreceptor- and vein-cell formation. Conversely, overexpression of RSK dramatically suppressed the ERK-dependent differentiation, which was further augmented by mutations in the Ras/ERK pathway. Consistent with these physiological phenotypes, RSK negatively regulated ERK-mediated developmental processes and gene expressions by blocking the nuclear localization of ERK in a kinase activity-independent manner. Moreover, I further demonstrated that the RSK-dependent inhibition of ERK nuclear migration is mediated by the physical association between ERK and RSK. 2) Mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP-3) is a well-known negative regulator in the Ras/ERK signaling pathway. Here, I demonstrated the physiological function of endogenous MKP-3 through the loss-of-function and null mutant-based studies. Although the DMKP-3 hypomorphic mutants well survived into adults with extra photoreceptor- and vein-cells, DMKP-3 null mutants showed embryonic lethality and severe oogenesis defects, demonstrating that MKP-3 is essential for the normal development in Drosophila. All of these phenotypes were highly similar to those of the gain-of-function mutants of ERK, and the functional interaction between MKP-3 and the Ras/ERK pathway was further confirmed by genetic interaction assays. 3) To find novel suppressors of the NF-kB signaling pathway, I performed a genetic screening for Drosophila mutants with hyper-activated immune responses, and isolated a loss-of-function mutant of caspa...