Published online before print April 19, 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: ajpath.2007.061277v1 170/6/2055    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ilic, D. Articles by Mauro, T. M. Search for Related Content PubMed Articles by Ilic, D. Articles by Mauro, T. M.

(American Journal of Pathology. 2007;170:2055-2067.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061277

Focal Adhesion Kinase Controls pH-Dependent Epidermal Barrier Homeostasis by Regulating Actin-Directed Na⁺/H⁺ Exchanger 1 Plasma Membrane Localization

Dusko Ilic^*, Man Mao-Qiang^*, Debra Crumrine^*, Gregory Dolganov, Nicholas Larocque, Pu Xu^*, Marianne Demerjian^*, Barbara E. Brown^*, Ssang-Taek Lim, Valeria Ossovskaya^¶, David D. Schlaepfer, Susan J. Fisher, Kenneth R. Feingold^||, Peter M. Elias^* and Theodora M. Mauro^*

From the Dermatology^* and Metabolism Service,|| Veteran Affairs Medical Center, San Francisco; the Departments of Pulmonary, Cell and Tissue Biology, and Anatomy,^¶ University of California, San Francisco; and the Department of Immunology, The Scripps Research Institute, La Jolla, California

Ubiquitously expressed focal adhesion kinase (FAK), linked to multiple intracellular signaling pathways, has previously been shown to control cell motility, invasion, proliferation, and survival. Using mice with a keratinocyte-restricted deletion of fak (FAK^{K5 KO}), we report here a novel role for FAK: maintenance of adult epidermal permeability barrier homeostasis. Abundant lacunae of unprocessed lipids in stratum corneum (SC) of FAK^{K5 KO} mice and delayed barrier recovery pointed to malfunction of pH-dependent enzymes active in extracellular space of SC. Measuring the SC pH gradient showed significantly more neutral pH values in FAK^{K5 KO} mice, suggesting the importance of FAK for acidification. Moreover, normal functions were restored when FAK^{K5 KO} mice were exposed to a surface pH typical of mouse SC (pH = 5.5). Baseline levels and response to barrier disruption of secretory phospholipase A2 isoforms, enzymes that mediate generation of free fatty acids in epidermis, appeared similar in both FAK^{K5 KO} and control littermates. We found that the critical SC acidification regulator Na⁺/H⁺ exchanger 1 failed to localize to the plasma membrane in FAK-deficient keratinocytes both in vivo and in vitro. Thus, for plasma membrane localization in terminally differentiated keratinocytes, Na⁺/H⁺ exchanger 1 requires an intact actin cytoskeleton, which is impaired in FAK-deficient cells.