Sci. STKE, 25 July 2006
DEVELOPMENT Conventional RSK Role at Risk
The p90 ribosomal protein S6 kinase (RSK) is a well-characterized direct target of the ERK mitogen-activated protein kinases. Phosphorylation by ERKs activates RSK and, in turn, RSK is thought to modify downstream targets by phosphorylation. The physiological relevance of all of this has been difficult to establish, in part because mammals have at least four isoforms of RSK. Kim et al. therefore turned to Drosophila, which have only one gene for RSK, and explored the effects of null and gain-of-function mutants. The unexpected result was that loss of RSK caused developmental defects just like those caused by excessive ERK-dependent signaling, whereas overexpression of RSK inhibited ERK-dependent wing and eye development. Thus, an essential role of RSK seems to be keeping ERK activity in check. Furthermore, this action of RSK appears not even to require its enzymatic activity. Mammalian ERK enzymes interact with RSK through a common docking (CD) domain, and this interaction appears to be conserved in Drosophila. Mutation of the interacting domain of RSK led to mislocalization of ERK to the nucleus. In fact, this interaction, which serves to retain ERK in the cytoplasm, rather than the kinase activity of RSK, appears to be its critical function in the fly. A catalytically inactive mutant still suppressed the developmental phenotypes of RSK-null flies, whereas a mutant of the CD domain that abolished interaction did not. The authors are forced to conclude that, rather than a mediator of ERK signals, RSK, at least in flies, is a negative regulator of ERK signaling that acts by sequestering ERK in the cytoplasm.
M. Kim, J. H. Lee, H. Koh, S. Y. Lee, C. Jang, C. J. Chung, J. H. Sung, J. Blenis, J. Chung, Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development. EMBO J. 25, 3056-3067 (2006). [PubMed]
Citation: Conventional RSK Role at Risk. Sci. STKE 2006, tw247 (2006).
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