Editors' ChoiceCell Biology

K-Ras Takes Sides

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Sci. Signal.  14 Jan 2014:
Vol. 7, Issue 308, pp. ec15
DOI: 10.1126/scisignal.2005065

Apoptotic epithelial cells are generally extruded from the apical surface of the sheet; healthy cells that are extruded apically undergo anoikis and die. Sphingosine 1-phosphate (S1P) produced by extruding cells signals through its receptor S1P2 on neighboring cells to induce basolateral contraction of an intercellular actomyosin network that pushes the cell out of the sheet apically and seals the hole left by extrusion. Slattum et al. report that Madin-Darby canine kidney (MDCK) cells expressing the oncogenic K-RasV12 allele—but not wild-type (WT) cells or those expressing the WT K-Ras allele (K-RasWT)—were preferentially extruded basally whether their extrusion was driven by an apoptotic stimulus (ultraviolet irradiation) or overcrowding. Although S1P was present at the interface between WT cells that were extruding apically and their neighbors, there was no S1P present around WT or K-RasV12 cells that were extruding basally. Treating WT MDCK cultures with an S1P2 antagonist reduced the overall rate of cell extrusion and changed the preferred direction of extrusion from apical to basal. Additional experiments indicated that this apparent switch in direction resulted from inhibition of apical extrusion with no effect on the infrequent basal extrusion events that normally occur in WT cells. Neither biosynthesis nor degradation of S1P was affected in K-RasV12 cells, but K-RasV12 cells exhibited increased autophagy compared with WT and K-RasWT–expressing cells. Inducing autophagy in WT cells promoted their basal extrusion, and inhibiting autophagy in K-RasV12 cells rescued both apical extrusion and S1P production, leading the authors to propose that autophagic degradation depleted S1P in K-RasV12 cells. In three-dimensional culture, MDCK cells form cysts in which the apical surfaces of the cells face the lumen of the cyst and the basal surfaces correspond to the outside of the cyst. Live cell imaging revealed that cells extruded apically from WT MDCK cysts underwent apoptosis in the lumen, but cells extruded apically from K-RasV12 cysts persisted in the lumen. Furthermore, cells extruded basally from K-RasV12 cysts survived and either migrated away from the cyst or proliferated to give rise to miniature cysts associated with the outer surface of the parent cyst. The finding that cells expressing the oncogenic K-RasV12 allele are preferentially extruded basally and not only survive extrusion but continue to proliferate after leaving the sheet offers a potential mechanism by which cells can metastasize from K-RasV12–expressing tumors.

G. Slattum, Y. Gu , R. Sabbadini, J. Rosenblatt, Autophagy in oncogenic K-Ras promotes basal extrusion of epithelial cells by degrading S1P. Curr. Biol. 24, 19–28 (2014). [PubMed]