title: The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKC&alpha; signaling.
abstract: Darier's disease (DD) is an inherited autosomal-dominant skin disorder characterized histologically by loss of adhesion between keratinocytes. DD is typically caused by mutations in sarcoendoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), a major regulator of intracellular Ca(2+) homeostasis in the skin. However, a defined role for SERCA2 in regulating intercellular adhesion remains poorly understood. We found that diminution of SERCA2 function by pharmacological inhibition or siRNA silencing in multiple human epidermal-derived cell lines was sufficient to disrupt desmosome assembly and weaken intercellular adhesive strength. Specifically, SERCA2-deficient cells exhibited up to a 60% reduction in border translocation of desmoplakin (DP), the desmosomal cytolinker protein necessary for intermediate filament (IF) anchorage to sites of robust cell-cell adhesion. In addition, loss of SERCA2 impaired the membrane translocation of protein kinase C α (PKCα), a known regulator of DP-IF association and desmosome assembly, to the plasma membrane by up to 70%. Exogenous activation of PKCα in SERCA2-deficient cells was sufficient to rescue the defective DP localization, desmosome assembly, and intercellular adhesive strength to levels comparable to controls. Our findings indicate that SERCA2-deficiency is sufficient to impede desmosome assembly and weaken intercellular adhesive strength via a PKCα-dependent mechanism, implicating SERCA2 as a novel regulator of PKCα signaling.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Hobbs
authors.forename: Evangeline V
authors.initials: EV
authors.lastname: Amargo
authors.forename: Agila
authors.initials: A
authors.lastname: Somasundaram
authors.forename: Cory L
authors.initials: CL
authors.lastname: Simpson
authors.forename: Murali
authors.initials: M
authors.lastname: Prakriya
authors.forename: Mitchell F
authors.initials: MF
authors.lastname: Denning
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D007644:Darier Disease / Q000378:metabolism* / Q000473:pathology; D051180:Desmoplakins / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D009062:Mouth Neoplasms; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D034741:RNA, Small Interfering; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C495294:DSP protein, human; D051180:Desmoplakins; D034741:RNA, Small Interfering; D007633:Keratins; D051571:Protein Kinase C-alpha; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D002118:Calcium