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

Early events in cell adhesion and polarity during epithelial-mesenchymal transition

“…Plakophilin 2, which regulates intercellular junction assembly, is a crucial scaffold for PKCa (Bass-Zubek et al, 2008). PKCa signaling also regulates the dynamics of desmoplakin through the Ca 2+ ATPase SERCA2 (also known as ATP2A2), which stabilizes desmosomes (Hobbs et al, 2011). However, plakoglobin, which is structurally related to b-catenin, can be phosphorylated at both tyrosines and serines (Gaudry et al, 2001;Shibamoto et al, 1994).…”

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

“…Desmogleins (DSG1-4) and desmocollins (DSC1-3) are cadherin superfamily proteins located in desmosomes. Previous studies have demonstrated that desmosomes are affected by calcium influx into the cell (28) and that homophilic and heterophilic interactions between DSC and DSG proteins generate cell aggregation (29,30). It has also been shown that desmosomal protein expression may be altered during cancer development (31,32) and may regulate cell proliferation (33).…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…In terms of this concept, it is of great interest to note, as the fi rst step of PV-affected desmosome remodeling, that PV-IgG activates PKC , which is located at desmosomal plaques when activated (Garrod et al, 2005) and can alter the stable hyper-adhesive desmosomes to dynamic weak-adhesive desmosomes (Sharpe et al, 1989;Hobbs et al, 2011). These PKC-dependent events lead keratinocytes to become more sensitive to blistering processes, that is, depletion and non-assembly of Dsg3 in desmosomes (Figure 4).…”