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

Background: Regulated secretion by mast cells is known to be controlled by GTP-binding proteins, but the proteins involved have not been identified. Rac and Rho, two small GTPases related to the oncoprotein Ras, mediate transmission of signals from cell-surface receptors to the actin 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 polymerization of actin filaments in the cell interior, whereas Rac is required for the entrapment in the interior of filaments released from the cortex. Such cytoskeletal changes could be: important in control of the exocytotic process, so we examined whether Rac and Rho also play a role in regulated secretion by mast cells. Results: We show that the constitutively active mutant proteins, V14RhoA acid V12Rac1, enhance regulated secretion from permeabilized mast cells by increasing the proportion of cells that are competent to respond to stimulation. In addition, inhibition of endogenous Rac and Rho activity using inhibitors, N17Rac1 and C3 transferase, respectively, reduces the secretory response of mast cells to stimuli. Conclusion: These results provide direct evidence that, in mast cells, both Rac and Rho are components of the signalling pathway that leads to secretion.