Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development

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Abstract
Although p90 ribosomal S6 kinase (RSK) is known as an important downstream effector of the ribosomal protein S6 kinase/extracellular signal‐regulated kinase (Ras/ERK) pathway, its endogenous role, and precise molecular function remain unclear. Using gain‐of‐function and null mutants of RSK, its physiological role was successfully 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. In addition, we further demonstrated that the RSK‐dependent inhibition of ERK nuclear migration is mediated by the physical association between ERK and RSK. Collectively, our study reveals a novel regulatory mechanism of the Ras/ERK pathway by RSK, which negatively regulates ERK activity by acting as a cytoplasmic anchor in Drosophila .