Abstract
Darier's disease (DD), caused by mutations in the endoplasmic reticulum (ER) Ca(2+) ATPase ATP2A2 (SERCA2b), is a skin disease that exhibits impaired epidermal cell-to-cell adhesion and altered differentiation. Although previous studies have shown that keratinocyte Ca(2+) sequestration and fluxes are controlled by sphingolipid signaling, the role of this signaling pathway in DD previously has not been investigated. We show here that sphingosine levels increase and sphingosine kinase (SPHK1) expression decreases after inactivating SERCA2b with the specific SERCA2 inhibitors thapsigargin (TG) or small interfering RNA to SERCA2b. Conversely, inhibiting sphingosine lyase rescues the defects in keratinocyte differentiation, E-cadherin localization, desmoplakin (DP) translocation, and ER Ca(2+) sequestration seen in TG-treated keratinocytes. Here, we report early evidence that the keratinocyte sphingolipid and Ca(2+) signaling pathways intersect in ATP2A2-controlled ER Ca(2+) sequestration, E-cadherin and DP localization, and Ca(2+)-controlled differentiation, and thus may be important mediators in DD.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Cadherins / metabolism
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Calcium / physiology*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cells, Cultured
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Darier Disease / drug therapy
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Darier Disease / physiopathology*
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Desmoplakins / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Keratinocytes / pathology*
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Mutation / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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RNA, Small Interfering / pharmacology
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / physiology*
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Signal Transduction / physiology*
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Sphingolipids / physiology*
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Thapsigargin / pharmacology
Substances
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Cadherins
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Desmoplakins
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Enzyme Inhibitors
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RNA, Small Interfering
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Sphingolipids
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Thapsigargin
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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ATP2A2 protein, human
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Calcium