SERCA2-controlled Ca2+-dependent Keratinocyte Adhesion and Differentiation is Mediated via the Sphingolipid Pathway- a Novel Therapeutic Target for Darier’s Disease

Autor: Daniel D. Bikle, Donald S. Mackenzie, Walter M. Holleran, Yoshikazu Uchida, Anna Celli, Yongjiao Zhai, Chia-Ling Tu, Theodora M. Mauro
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Keratinocytes
Cellular differentiation
Sphingosine kinase
Biochemistry
030207 dermatology & venereal diseases
chemistry.chemical_compound
0302 clinical medicine
Enzyme Inhibitors
RNA
Small Interfering
Cells
Cultured
Calcium signaling
0303 health sciences
desmoplakin
apoptosis
Cell Differentiation
Cadherins
3. Good health
Cell biology
Phosphotransferases (Alcohol Group Acceptor)
medicine.anatomical_structure
Darier’s Disease
Thapsigargin
Signal transduction
Keratinocyte
Signal Transduction
keratinocyte
Dermatology
Biology
Article
Sarcoplasmic Reticulum Calcium-Transporting ATPases
03 medical and health sciences
medicine
Cell Adhesion
Humans
Calcium Signaling
Molecular Biology
acantholysis
030304 developmental biology
Sphingolipids
calcium
Sphingosine
E-cadherin
Cell Biology
Molecular biology
Sphingolipid
chemistry
Desmoplakins
Mutation
sphingolipid
Darier Disease
Zdroj: The Journal of investigative dermatology
ISSN: 1523-1747
0022-202X
Popis: Summary Darier’s Disease (DD), caused by mutations in the endoplasmic reticulum (ER) Ca2+ 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 Ca2+ 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 siRNA to SERCA2b. Conversely, inhibiting sphingosine lyase rescues the defects in keratinocyte differentiation, E-cadherin localization, Desmoplakin (DP) translocation, and ER Ca2+ sequestration seen in TG-treated keratinocytes. To our knowledge, it was previously unreported that the keratinocyte sphingolipid and Ca2+ signaling pathways intersect in ATP2A2- controlled ER Ca2+ sequestration, E-cadherin and desmoplakin localization and Ca2+ - controlled differentiation, and thus may be important mediators in DD.
Databáze: OpenAIRE
Externí odkaz: