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© The Rockefeller University Press, 0021-9525/2000//481 $5.00
The Journal of Cell Biology, Volume 148, Number 3, , 2000 481-494

Original Article

Cdc42 and Rac Stimulate Exocytosis of Secretory Granules by Activating the Ip3/Calcium Pathway in Rbl-2h3 Mast Cells



Elizabeth Hong-Gellera and Richard A. Cerionea

a Department of Molecular Medicine, Cornell University, Ithaca, New York 14853
Veterinary Medical Center C3-155, Cornell University, Ithaca, NY 14853.(607) 253-3659(607) 253-3888

rac1{at}cornell.edu

We have expressed dominant-active and dominant-negative forms of the Rho GTPases, Cdc42 and Rac, using vaccinia virus to evaluate the effects of these mutants on the signaling pathway leading to the degranulation of secretory granules in RBL-2H3 cells. Dominant-active Cdc42 and Rac enhance antigen-stimulated secretion by about twofold, whereas the dominant-negative mutants significantly inhibit secretion. Interestingly, treatment with the calcium ionophore, A23187, and the PKC activator, PMA, rescues the inhibited levels of secretion in cells expressing the dominant-negative mutants, implying that Cdc42 and Rac act upstream of the calcium influx pathway. Furthermore, cells expressing the dominant-active mutants exhibit elevated levels of antigen-stimulated IP3 production, an amplified antigen-stimulated calcium response consisting of both calcium release from internal stores and influx from the extracellular medium, and an increase in aggregate formation of the IP3 receptor. In contrast, cells expressing the dominant-negative mutants display the opposite phenotypes. Finally, we are able to detect an in vitro interaction between Cdc42 and PLC{gamma}1, the enzyme immediately upstream of IP3 formation. Taken together, these findings implicate Cdc42 and Rac in regulating the exocytosis of secretory granules by stimulation of IP3 formation and calcium mobilization upon antigen stimulation.

Key Words: Cdc42p • Rac • calcium signaling • degranulation • signal transduction

© 2000 The Rockefeller University Press

Abbreviations used in this paper: FAK, focal adhesion kinase; IP3, inositol 1,4,5-trisphosphate; PBD, Cdc42/Rac (p21)-binding domain; PI3-K, phosphoinositide 3-kinase; PIP2-4,5, phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PLC{gamma}, phospholipase C-{gamma}.


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