Editors' ChoiceCell Biology

Putting the squeeze on ERK signaling

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Sci. Signal.  22 Jan 2019:
Vol. 12, Issue 565, eaaw6857
DOI: 10.1126/scisignal.aaw6857

Cell compaction induces epithelial cell elimination by reducing ERK activation.

Epithelial cells that are damaged or infected are extruded from the epithelial sheet and undergo apoptosis. Caspase activation precedes and is required for extrusion. This process also contributes to tissue homeostasis by eliminating excess cells when the epithelium becomes crowded, such as at the midline of the developing pupal notum, which gives rise to the adult thorax, in Drosophila melanogaster. Moreno et al. found that the proapoptotic protein Hid, which acts upstream of caspases, was required for cell extrusion at the notum midline. Signaling from the epidermal growth factor receptor (EGFR) through the small GTPase Ras and the kinase Raf to extracellular signal–regulated kinase (ERK) promoted cell survival in the notum by inhibiting hid expression. ERK activation was reduced at the midline, where cells are crowded, and extrusion events are concentrated, compared with the rest of the notum. The amount of ERK signaling correlated with the degree of tissue deformation, with high ERK activity in areas of stretching and low ERK activity in areas of compaction. Different types of laser wounds that reduced epithelial surface tension or increased compaction caused an increase or reduction in ERK activity, respectively. ERK activation was also reduced in highly compacted cells between clones expressing an activated form of Ras (RasV12), which stimulates overgrowth. Although secreted factors were not involved in compaction-induced ERK inhibition and cell elimination, stimulating ERK activation with a secreted form of the EGFR ligand Spitz prevented compaction-induced cell elimination and slowed the expansion of RasV12 clones. Thus, the reduction of ERK activity is a mechanism by which mechanical forces can promote epithelial cell elimination, suggesting that reduced ERK activation in surrounding tissues may play a role in the expansion of Ras-driven epithelial cancers.

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