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Cortical localization of the small GTPase Rho1 activates the JNK signaling pathway to kill Drosophila epithelial cells, Neisch et al. reveal.
Cell death by apoptosis is elevated in flies missing the epithelial protein moesin, which organizes the apical cortex of cells, partly by linking the plasma membrane to the underlying actin cytoskeleton. Moesin also regulates Rho1, but the GTPase's contribution to apoptosis was unclear.
Neisch et al. saw that plasma membrane levels of Rho1 were increased in fly epithelia lacking moesin, and that removing one copy of the GTPase rescued the cells from apoptosis. In addition, overexpressing Rho1 boosted cell death by up-regulating the pro-apoptotic gene hid. The authors then investigated the JNK signaling pathway, which can promote apoptosis in Drosophila imaginal disc epithelia. The pathway was activated in the absence of moesin, and inhibiting different steps of the signaling cascade blocked Rho1-induced death. Rho1 activated JNK signaling through an interaction with an upstream kinase called Slipper, but surprisingly, this association was independent of whether Rho1 was bound to GTP or GDP.
Recruitment of Rho1 and Slipper to the cell cortex was essential to triggering apoptosis in cells lacking moesin, as the two proteins formed a complex with other components of the JNK signaling pathway. The next step, says senior author Richard Fehon, is to determine how moesin limits the amount of Rho1 at the cell membrane and whether this is controlled developmentally. One possibility is that moesin binds a GTPase-activating protein to switch off Rho1 and decrease its membrane association.