Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells

In vertebrates, newly emerging transformed cells are often apically extruded from epithelial layers through cell competition with surrounding normal epithelial cells. However, the underlying molecular mechanism remains elusive. Here, using phospho-SILAC screening, we show that phosphorylation of AHNAK2 is elevated in normal cells neighboring RasV12 cells soon after the induction of RasV12 expression, which is mediated by calcium-dependent protein kinase C. In addition, transient upsurges of intracellular calcium, which we call calcium sparks, frequently occur in normal cells neighboring RasV12 cells, which are mediated by mechanosensitive calcium channel TRPC1 upon membrane stretching. Calcium sparks then enhance cell movements of both normal and RasV12 cells through phosphorylation of AHNAK2 and promote apical extrusion. Moreover, comparable calcium sparks positively regulate apical extrusion of RasV12-transformed cells in zebrafish larvae as well. Hence, calcium sparks play a crucial role in the elimination of transformed cells at the early phase of cell competition. [Display omitted] •Phosphorylation of AHNAK2 is elevated in normal cells neighboring transformed cells•TRPC1-mediated calcium sparks in normal cells mediate the AHNAK2 phosphorylation•Calcium sparks promote tissue fluidity and apical extrusion of transformed cells•Comparable calcium sparks regulate apical extrusion in cultured cells and zebrafish Kuromiya et al. use mammalian cell culture and zebrafish systems to show that calcium sparks frequently occur in normal epithelial cells neighboring RasV12-transformed cells at the early phase of cell competition. Calcium sparks then promote epithelial tissue fluidity and apical extrusion of transformed cells through the phosphorylation of AHNAK2.