Focal adhesion kinase controls pH-dependent epidermal barrier homeostasis by regulating actin-directed Na+/H+ exchanger 1 plasma membrane localization.
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.
Ilic
Dusko
D
Dermatology Service, Veterans Affairs Medical Center, San Francisco, CA, USA. dilic@stemlifeline.com
Mao-Qiang
Man
M
Crumrine
Debra
D
Dolganov
Gregory
G
Larocque
Nicholas
N
Xu
Pu
P
Demerjian
Marianne
M
Brown
Barbara E
BE
Lim
Ssang-Taek
ST
Ossovskaya
Valeria
V
Schlaepfer
David D
DD
Fisher
Susan J
SJ
Feingold
Kenneth R
KR
Elias
Peter M
PM
Mauro
Theodora M
TM
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism* / Q000648:ultrastructure; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012697:Serine Endopeptidases / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D012697:Serine Endopeptidases