The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signaling

FASEB J. 2011 Mar;25(3):990-1001. doi: 10.1096/fj.10-163261. Epub 2010 Dec 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Carcinoma, Squamous Cell
  • Cell Adhesion / physiology
  • Cell Communication / physiology
  • Cell Line, Tumor
  • Darier Disease / metabolism*
  • Darier Disease / pathology
  • Desmoplakins / metabolism*
  • Desmosomes / metabolism
  • Desmosomes / pathology
  • Humans
  • Intermediate Filaments / metabolism
  • Keratins / metabolism
  • Mouth Neoplasms
  • Protein Kinase C-alpha / metabolism*
  • RNA, Small Interfering
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Signal Transduction / physiology*


  • DSP protein, human
  • Desmoplakins
  • RNA, Small Interfering
  • Keratins
  • Protein Kinase C-alpha
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human
  • Calcium