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Vol. 17, Issue 11, 4925-4935, November 2006

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4 Integrin and Epidermal Growth Factor Coordinately Regulate Electric Field-mediated Directional Migration via Rac1

Christine E. Pullar^*,, Brian S. Baier^*, Yoshinobu Kariya, Alan J. Russell^,, Basil A.J. Horst^,||, M. Peter Marinkovich^,¶, and R. Rivkah Isseroff^*,#

*Department of Dermatology, University of California, Davis, Davis, CA 95616; Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305; ^#Dermatology Service, Northern California Health Care System, Department of Veterans Affairs, Mather, CA 95655; and ^¶VA Palo Alto Health Care System, Department of Veterans Affairs, Stanford, CA 94304

Submitted May 24, 2006; Revised July 21, 2006; Accepted August 9, 2006
Monitoring Editor: Mark Ginsberg

Endogenous DC electric fields (EF) are present during embryogenesis and are generated in vivo upon wounding, providing guidance cues for directional cell migration (galvanotaxis) required in these processes. To understand the role of beta ()4 integrin in directional migration, the migratory paths of either primary human keratinocytes (NHK), 4 integrin-null human keratinocytes (4–), or those in which 4 integrin was reexpressed (4+), were tracked during exposure to EFs of physiological magnitude (100 mV/mm). Although the expression of 4 integrin had no effect on the rate of cell movement, it was essential for directional (cathodal) migration in the absence of epidermal growth factor (EGF). The addition of EGF potentiated the directional response, suggesting that at least two distinct but synergistic signaling pathways coordinate galvanotaxis. Expression of either a ligand binding–defective 4 (4+AD) or 4 with a truncated cytoplasmic tail (4+CT) resulted in loss of directionality in the absence of EGF, whereas inhibition of Rac1 blinded the cells to the EF even in the presence of EGF. In summary, both the 4 integrin ligand–binding and cytoplasmic domains together with EGF were required for the synergistic activation of a Rac-dependent signaling pathway that was essential for keratinocyte directional migration in response to a galvanotactic stimulus.

Present addresses: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom;

Molecular and Cellular Biology, Cytokinetics Inc., 280 East Grand Avenue, South San Francisco, CA 94080;

^|| Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 11032.

Address correspondence to: R. Rivkah Isseroff (rrisseroff{at}ucdavis.edu)

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