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© The Rockefeller University Press, 0021-9525/2000//785 $5.00
The Journal of Cell Biology, Volume 150, Number 4, , 2000 785-796

Two Pathways through Cdc42 Couple the N-Formyl Receptor to Actin Nucleation in Permeabilized Human Neutrophils

^a Hematology Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
Hematology Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Room 301, 221 Longwood Avenue, Boston, MA 02115.(617) 734-2248(617) 278-0389

mglogauer{at}rics.bwh.harvard.edu

We developed a permeabilization method that retains coupling between N-formyl-methionyl-leucyl-phenylalanine tripeptide (FMLP) receptor stimulation, shape changes, and barbed-end actin nucleation in human neutrophils. Using GTP analogues, phosphoinositides, a phosphoinositide-binding peptide, constitutively active or inactive Rho GTPase mutants, and activating or inhibitory peptides derived from neural Wiskott-Aldrich syndrome family proteins (N-WASP), we identified signaling pathways leading from the FMLP receptor to actin nucleation that require Cdc42, but then diverge. One branch traverses the actin nucleation pathway involving N-WASP and the Arp2/3 complex, whereas the other operates through active Rac to promote actin nucleation. Both pathways depend on phosphoinositide expression. Since maximal inhibition of the Arp2/3 pathway leaves an N17Rac inhibitable alternate pathway intact, we conclude that this alternate involves phosphoinositide-mediated uncapping of actin filament barbed ends.

Key Words: Arp2/3 • actin assembly • signal transduction pathways • Rac • FMLP

© 2000 The Rockefeller University Press

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