THE SMALL GTPASES RAC AND RHO AS REGULATORS OF SECRETION IN MAST-CELLS

Background: Regulated secretion by mast cells is known to be controlle d by GTP-binding proteins, but the proteins involved have not been ide ntified. Rac and Rho, two small GTPases related to the oncoprotein Ras , mediate transmission of signals from cell-surface receptors to the a ctin cytoskeleton. In rat mast cells, both Rac and Rho participate in effecting the centripetal redistribution of filamentous actin that is observed after stimulation of the cells. Rho is responsible for polyme rization of actin filaments in the cell interior, whereas Rac is requi red for the entrapment in the interior of filaments released from the cortex. Such cytoskeletal changes could be: important in control of th e exocytotic process, so we examined whether Rac and Rho also play a r ole in regulated secretion by mast cells. Results: We show that the co nstitutively active mutant proteins, V14RhoA acid V12Rac1, enhance reg ulated secretion from permeabilized mast cells by increasing the propo rtion of cells that are competent to respond to stimulation. In additi on, inhibition of endogenous Rac and Rho activity using inhibitors, N1 7Rac1 and C3 transferase, respectively, reduces the secretory response of mast cells to stimuli. Conclusion: These results provide direct ev idence that, in mast cells, both Rac and Rho are components of the sig nalling pathway that leads to secretion.