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Published online November 5, 2007
doi:10.1083/jcb.200704169
The Journal of Cell Biology, Vol. 179, No. 3, 403-410
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Frantz et al.
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Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells



Christian Frantz1, Anastasios Karydis1, Perihan Nalbant2, Klaus M. Hahn3, and Diane L. Barber1

1 Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143
2 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
3 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599

Correspondence to Diane L. Barber: diane.barber{at}ucsf.edu

A fundamental feature of cell polarity in response to spatial cues is asymmetric amplification of molecules generated by positive feedback signaling. We report a positive feedback loop between the guanosine triphosphatase Cdc42, a central determinant in eukaryotic cell polarity, and H+ efflux by Na-H+ exchanger 1 (NHE1), which is necessary at the front of migrating cells for polarity and directional motility. In response to migratory cues, Cdc42 is not activated in fibroblasts expressing a mutant NHE1 that lacks H+ efflux, and wild-type NHE1 is not activated in fibroblasts expressing mutationally inactive Cdc42-N17. H+ efflux by NHE1 is not necessary for release of Cdc42–guanosine diphosphate (GDP) from Rho GDP dissociation inhibitor or for the membrane recruitment of Cdc42 but is required for GTP binding by Cdc42 catalyzed by a guanine nucleotide exchange factor (GEF). Data indicate that GEF binding to phosphotidylinositol 4,5–bisphosphate is pH dependent, suggesting a mechanism for how H+ efflux by NHE1 promotes Cdc42 activity to generate a positive feedback signal necessary for polarity in migrating cells.

Abbreviations used in this paper: CRIB, Cdc42/Rac-interactive binding domain; Dbs, Dbl's big sister; DH, Dbl homology; GEF, guanine nucleotide exchange factor; mant, methylanthraniloyl; MeroCBD, merocyanine–Cdc42-binding domain; NHE1, Na-H+ exchanger 1; PAK, p21-activated kinase; PH, pleckstrin homology; pHi, intracellular pH; PI(4,5)P2, phosphotidylinositol 4,5–bisphosphate; RhoGDI, Rho GDP dissociation inhibitor; WT, wild type.


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