title: SERCA2-controlled Ca²+-dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway: a therapeutic target for Darier's disease.
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.
authors.affiliation: Department of Dermatology, San Francisco Veterans Administration Medical Center, San Francisco, California 94121-1545, USA. celli.anna@gmail.com
authors.forename: Anna
authors.initials: A
authors.lastname: Celli
authors.forename: Donald S
authors.initials: DS
authors.lastname: Mackenzie
authors.forename: Yongjiao
authors.initials: Y
authors.lastname: Zhai
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Tu
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Theodora M
authors.initials: TM
authors.lastname: Mauro
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D007644:Darier Disease / Q000188:drug therapy / Q000503:physiopathology*; D051180:Desmoplakins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013107:Sphingolipids / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D015820:Cadherins; D002118:Calcium; D051180:Desmoplakins; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013107:Sphingolipids; D019284:Thapsigargin; D000099157:Sphingosine Kinase; C506946:ATP2A2 protein, human