Journal of Lipid Research Volume 54, 2013 581characterized by growth arrest and expression of the mature keratins 1 and 10 in the fi rst differentiated layer of the epidermis, the spinous layer. Early differentiation in the spinous layer is followed by further differentiation in the granular layer, which is accompanied by expression of proteins that are essential for the formation of the cornifi ed envelope and corneocytes. The corneocytes constitute the outer layer of the epidermis, the stratum corneum, and give skin its resilience to mechanical stress (as reviewed in Ref. 1 ). Defi ciencies in the mechanical barrier function of the epidermis result in skin diseases. For example, epidermolysis bullosa simplex and epidermolytic hyperkeratosis arise through mutations in keratins comprising the intermediate fi laments and are characterized by extensive blistering and epidermal sloughing as a result of the mechanical stresses encountered by routine interactions with the environment (as reviewed in Ref.2 ). Many tissues of the body in addition to the skin are exposed to mechanical stresses that result in tearing, or disrupting, the plasma membrane of the constituent cells. These disruptions will result in cell death if left unrepaired. However, cells possess an active plasma membrane repair process that can restore plasma membrane integrity if the disruption is not too extensive (as reviewed in Ref.3 ). For example, intestinal cells in the gastrointestinal tract are subjected to mechanical perturbations during the transit of a food bolus; these plasma membrane disruptions can be repaired to allow cell survival ( 4-6 ). Similarly, eccentric contraction of skeletal muscle as a result of downhill treadmill running induces plasma membrane disruptions that are largely repaired ( 7 ). Routine ambulation also appears to lead to plasma membrane disruptions in the epidermis of the digits ( 8 ). Therefore, it is critical that cells in these mechanically active tissues be able to repair membrane Keratinocytes form the epithelium of the skin, the epidermis, and comprise several cell layers. As keratinocytes migrate up from the stratum basale, they undergo a distinct pattern of differentiation that is essential for the function of the skin as a protective barrier. This pattern is Abbreviations: 1,25(OH) 2 D 3 , 1,25-dihydroxyvitamin D 3 ; AQP3, aquaporin 3; FIPI, 5-fl uoro-2-indolyl des-chlorohalopemide; HBSS, Hank's buffered salt solution; K-SFM, keratinocyte serum-free medium; PEt, phosphatidylethanol; PG, phosphatidylglycerol; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PLD, phospholipase D; SFKM, serum-free keratinocyte medium; TPA, 12-O -tetradecanoylphorbol 13-acetate.