Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101583


Historic Background

Desmoglein-3 (Dsg3) was first identified as a pemphigus vulgaris antigen (PVA) from the human keratinocyte expression libraries in 1991 by Amagai et al. in an attempt to search for the targets of pemphigus vulgaris autoantibodies (Amagai et al. 1991). Due to its significant homology with the cadherin family of cell adhesion molecules and most remarkably to Dsg1, Dsg3 is characterized as a member of cadherin superfamily and specifically the one in desmoglein subfamily which contains Dsg1. Pemphigus vulgaris (PV) is a potentially lethal autoimmune blistering disease that affects oral mucosa and skin with the manifestation of acantholysis characterized as the loss of adhesion between epithelial cells and structural components maintaining cell cohesion in the tissues caused by the action of autoantibodies against Dsg3 as well as Dsg1. Dsg1 is also a target antigen in another autoantibody-mediated blistering disease of the skin,  pemphigus foliaceus. There are two subfamilies of desmosomal cadherins, desmoglein (Dsg) and desmocollin (Dsc), both of which are members of the cadherin superfamily of calcium-dependent adhesive proteins in desmosomes, one type of intercellular junctions between epithelial, myocardial, and other cell types that confer strong cell–cell adhesion (Thomason et al. 2010). There are four human desmoglein isoforms (Dsg1–4) and three desmocollin isoforms (Dsc1–3), which exhibit different tissue and cell type–specific expression patterns. For instance, Dsg3/Dsc3 and Dsg1/Dsc1 are more restricted to complex epithelial tissues, whereas Dsg2/Dsc2 are widely expressed in desmosomes of the basal layer of stratified epithelia, simple epithelia, and nonepithelial cells such as the cardiomyocytes and lymph node follicles. Dsg3, in particular, is found confined in the basal and immediate suprabasal layers of epidermis but uniformly distributed across the entire stratified squamous epithelia in the oral mucosa.

All the genes that encode Dsgs and Dscs are located within a tightly linked cluster in chromosome 18q12.1 (Frank et al. 2001). Although mutations in the human Dsg3 gene have not been described to date, mutations in DSG3 underlie the balding mice (Davisson et al. 1994; Pulkkinen et al. 2002) and overt squeaky phenotype with a spectrum of severe pathology such as cyclic hair loss, obstructed airways, and severe immunodeficiency subsequent to the development of oral lesions and malnutrition (Kountikov et al. 2015). The ablation of DSG3 gene in mice leads to fragility of the skin and oral mucous membrane, analogous to those found in PV patients, along with runting and hair loss (Koch et al. 1997, 1998). However, a recent report has revealed expression of a 31-kDa truncated protein of Dsg3 containing 282 amino acids, which corresponds to the N-terminal truncated intracellular domain of Dsg3, in differentiating keratinocytes of human epidermis (Lee et al. 2009b). This truncated Dsg3 was also found to be upregulated in psoriatic epidermis and skin tumors, including Bowen’s disease and squamous cell carcinoma (SCC). In addition, recently, upregulation of the Dsg3 gene and protein (wild type) has also been reported in cancer, especially in SCC with increased levels of expression correlating with the clinical stage of malignancy, implicating its procancerous role and potentiality to serve as a diagnostic and prognostic marker (Brown and Wan 2015).

The mature form of Dsg3 (50–999 amino acids) is cleaved from a precursor protein and contains the unglycosylated peptide of 950 amino acids. The first 23 amino acids are the signal peptide. Like other cadherins, Dsg3 is a single-pass transmembrane glycoprotein consisting of the extracellular domain with five motifs of about equal size, EC1 through EC5, which, except for EC5, have homology with each other, in particular among EC1 to EC3, the most amino-terminal domains. All five extracellular motifs that contain 566 amino acids (50–615 amino acids), also show significant homology with the corresponding region in classical cadherin, such as P-cadherin (Amagai et al. 1991). Both Dsg1 and Dsg3 have a RAL site (128–130 amino acids) in EC1 that corresponds to the conserved cell adhesion recognition sequence HAV in an equivalent position in classical cadherins that is responsible for homophilic binding. Other conserved sequences in the extracellular domain are several putative Ca2+-binding sites with all cadherins. The transmembrane region of Dsg3 encompasses 25 amino acids (616–640 amino acids) and the cytoplasmic domain contains 359 amino acids (641–999 amino acids) which is substantially longer than that of typical cadherins (approximately 150 residues) but shorter than that of Dsg1 (480 residues). The cytoplasmic tail consists of several domains, such as the intracellular anchoring domain (IA), intracellular cadherin-specific domain (ICS), proline-rich linker domain (IPL), repeating unit domain (RUD), and lastly the desmoglein-specific terminal domain (DTD). The proteins that have been identified to directly bind to the cytoplasmic domain of Dsg3 includes p120 that binds to IA, plakoglobin (Pg) and caveolin-1 (Cav-1) that bind to ICS, and actin with the specific domain not yet defined (Andl and Stanley 2001; Brown et al. 2014; Wan et al. 2016; Kanno et al. 2008). The evidence for the interaction with actin proteins came from the mass spectrometry analysis of the Halo immunoprecipitates from A431 cells transfected with plasmid containing the entire Dsg3 cytoplasmic tail tagged with Halo at the N-terminus (Brown et al. 2014). Dsg3 has also been found to form complexes with many other proteins, in particular the signal molecules that are described below. Although Dsg3 belongs to the desmoglein subfamily, it has been found to be uniformly distributed on keratinocyte cell surface of stratified squamous epithelia, suggesting that Dsg3 does not solely function in desmosome adhesion but rather plays an extrajunctional role associating with other cellular processes than cell–cell adhesion.

The evidence that suggests Dsg3 acting as a signaling molecule comes from plethora studies in pemphigus research over the past two decades that demonstrates that PV-IgG binding to Dsg3 on keratinocyte surface triggers a cascade of intracellular events, such as Dsg3 phosphorylation, activation of phospholipase C (PLC) signal pathway including production of inositol 1,4,5-trisphosphate (IP3) and induction of a Ca2+/PKC, signaling through p38MAPK/heat shock protein 27 (HSP27), Src, epidermal growth factor receptor (EGFR), apoptosis, c-Myc, adaptor protein plakoglobin/plakophinlin-3, as well as Rho GTPases and rearrangement of actin cytoskeleton, etc. All these observations have implicated a key role of Dsg3 in mediating outside-in signaling that leads to desmosome remodeling, cell proliferation and differentiation, or apoptosis. Deregulation of these signal pathways causes depletion of Dsg3 from the desmosomes and keratinocyte surface, resulting in cell dissociation and blister formation as observed in pemphigus disease. For convenience, the discussion below regarding the PV-IgG induced Dsg3 signaling is referred to as “PV-IgG signaling” in this review, unless otherwise specified.

Phospholipase C (PLC) and Protein Kinase C (PKC) Signaling

In 1995, Kitagima and his colleagues had made the first discovery that pemphigus IgGs, but not IgGs from bullous pemphigoid or normal sera, caused an induction of rapid and transient increase of Ca2+ and  inositol triphosphate (IP3) in cultured human keratinocytes, and this induction was correlated with secretion of plasminogen activator (PA) and disruption of cell–cell adhesions (Seishima et al. 1995). It was later demonstrated by the same group that PLC is actually involved in these events since preincubation of keratinocytes with a specific PLC inhibitor U73122 dramatically reduced the pemphigus IgG-induced increase in Ca2+ and IP3 as well as the PA activity and cell–cell detachment (Esaki et al. 1995). PLC mediates catalytic hydrolysis of phosphatidylinositol bisphosphate, generating IP3 and  diacylglycerol (DAG), with the former rendering an increase of intracellular Ca2+ and the latter activating protein kinase C (PKC), a family of Ca2+ and phospholipid-dependent serine/threonine kinases (Fig. 1). Indeed, in a time-course study on the involvement of PKCs in PV-IgG induced cell–cell detachment, the distribution of PKC isozymes, including conventional isoform PKC-alpha, novel PKC-delta and PKC-eta, and atypical PKC-zeta which are known to be expressed in human keratinocytes, was shown to be modulated in a time-dependent manner and all the PKC isozymes analyzed were translocated from the cytosol to the cytoskeletal fractions within 30 min after PV-IgG stimulation (Osada et al. 1997). Both PKC-alpha and PKC-delta were immediately translocated to the cytoskeletal-associated fractions within seconds, with a peak at 1 min and 5 min, respectively, and this increase gradually declined after 30 min. PKC-eta’s translocation, however, was induced slowly, taking more than 5 min, and was decreased to approximately half-maximum at 30 min. The PKC-zeta’s translocation reached a maximum at 30 s rapidly and returned to baseline after 5 min followed by PV-IgG stimulation. It was also shown that the activity of total PKCs in cytoskeletal fraction was increased too after PV-IgG exposure, with a peak at 1 min, and was sustained for at least 30 min. It was thus suggested that enhanced PKC activity in PV-IgG-treated keratinocytes may play a role in modulating desmosome turnover and dysfunction of hemidesmosomes through the mechanisms of serine phosphorylation of junctional proteins as well as secretion of urokinase-type PA and expression of its receptor uPAR (Kitajima et al. 1999). Furthermore, serine phosphorylation of Dsg3 was detected in cells treated with PV-IgG and this was accompanied by its dissociation from plakoglobin (Aoyama et al. 1999). Importantly, inhibition of PKC by either Gö6976 or safingo blocked PV-IgG-mediated depletion of Dsg3 in cultured human epidermis and blister formation in a neonatal mouse (Spindler et al. 2011). Together, these findings suggest that PV-IgG binding to Dsg3 stimulates PLC-signaling pathway and its downstream events, such as calcium release, PKC activation, uPA secretion, and its receptor expression, that collectively lead to the depletion of Dsg3 from the cell surface and the desmosomes followed by the disruption of cell cohesion and blister formation in keratinocytes both in vitro and in vivo (Fig. 1).
Desmoglein-3, Fig. 1

PLC and PKC signaling. Autoantibodies targeting Dsg3 on keratinocyte surface activate PLC and its downstream PKC (phosphorylation), leading to uPA secretion, Dsg3 phosphorylation, and ultimately cell–cell detachment

p38 MAPK Signaling

Strong evidence suggests that Dsg3 acts as an upstream regulator of p38 mitogen-activated protein kinase (MAPK), and this signaling pathway plays a crucial role in PV-IgG signaling that causes onset of pemphigus disease (Vielmuth et al. 2015; Kawasaki et al. 2006; Berkowitz et al. 2005, Berkowitz et al. 2006; Kitajima. 2014; Mao et al. 2011). This finding again originates from a plethora of pemphigus research that show autoantibodies from patients with PV and pemphigus foliaceus (PF) target Dsg3/Dsg1 and trigger the activation of p38 MAPK and its downstream HSP27 (Berkowitz et al. 2005, 2006, 2008a, b). When human keratinocytes were treated with pathogenic anti-Dsg3 autoantibodies, p38 MAPK and HSP27 were rapidly phosphorylated, in response to PV-IgG that can be abrogated by the pharmacological inhibition of p38 MAPK activity, and this finding was demonstrated in both in vitro and in vivo experiments. It is worth noting that this was further evaluated by an independent study using the characterized potent pathogenic monoclonal antibody against Dsg3 (AK23 mAb), and the treatment of human keratinocytes DJM-1 cells with AK23 caused augmented levels of p38 MAPK activity and concomitantly increased serine phosphorylation of Dsg3 (Kawasaki et al. 2006). The time-course study is critical by providing the insight of activation cascades stimulated by PV-IgG, and it was revealed that the activation of Src peaked at 30 min, EGF receptor kinase at 60 min, and p38 MAPK at 240 min after exposure of PV-IgG in keratinocytes (Chernyavsky et al. 2007). Inhibition of Src by its specific inhibitor PP1 showed only partial abrogation of the activity of EGFR kinase and p38 by approximately 45 and 30%, respectively, suggesting that Src is part of signaling events induced by PV-IgG signaling. In parallel to the p38 MAPK activation at approximately same time, cell surface Dsg3 was found to be internalized and translocated into endosomes followed by degradation in lysosome. Such a depletion of Dsg3 can be sufficiently blocked by p38 MAPK specific inhibitor SB202190 (Jolly et al. 2010; Vielmuth et al. 2015), suggesting that p38 activation is directly responsible for the endocytosis and degradation of Dsg3 followed by PV-IgG exposure. In line with this finding, another study provided the evidence that p38 MAPK is activated downstream to the loss of cell–cell adhesion (the secondary event) as both knockdown of p38 in cultured cells and p38-alpha ablation in animal model showed the surface Dsg3 retained in acantholysis cells treated with PV-IgG albeit there was blister formation (Mao et al. 2011). Correspondingly, exogenous expression of p38-accelerated Dsg3 internalization and degradation alongside other desmosomal proteins, desmocollin 3 and desmoplakin, indicating that p38 activation is responsible for desmosome disassembly and blister formation. Interestingly, another study indicates that such p38 MAPK-mediated endocytosis of surface Dsg3 is caused only by pathogenic polyclonal PV-IgG but not by pathogenic monoclonal antibodies that are capable of inducing compromised cell adhesion strength but unable to cause Dsg3 clustering and endocytosis (Saito et al. 2012). Furthermore, it has been identified that (mitogen-activated protein kinase-activated protein) kinase 2 (MK2) acts as a key downstream effecter of p38 signaling in PV (Mao et al. 2014). Altogether, these findings underscore that polyclonal antibodies targeting Dsg3 trigger a cascade of intracellular signaling involving p38 MAPK activation that plays a central part in the PV-IgG induced Dsg3 depletion, desmosome dissolution, and pemphigus acantholysis, as illustrated in Fig. 2. The consequence of such signaling events is the keratinocyte cell shrinkage and apoptosis leading to accelerated acantholysis and blistering presented in pemphigus disease (Lee et al. 2009a) (discussed below).
Desmoglein-3, Fig. 2

PV-IgG targeting Dsg3 on keratinocytes induces Src phosphorylation and activation of p38 pathway that in turn causes desmosome disassembly and cell apoptosis that lead to blistering and pemphigus acantholysis in skin and oral mucosa. Dissociation of Pg from Dsg3 is also a concurrent event in PV-IgG signaling

EGF Receptor and Apoptosis Pathways

It has been shown that p38 MAPK activation not only stimulates but also enhances cell apoptosis in PV-IgG-treated keratinocytes, in PV patients, and also in passive transfer model, suggesting that apoptosis could be a major causal factor of the acantholytic phenomenon (Lee et al. 2009a; Pelacho et al. 2004; Wang et al. 2004; Grando et al. 2009). The observations of apoptosis in PV includes (1) secretion of soluble FasL; (2) elevated cellular amounts of FasR, FasL, Bax, and p53 proteins; (3) reduction in the levels of cellular Bcl-2; (4) enrichment in caspase 8 and activation of caspases 1 and 3; and (5) coaggregation of FasL and FasR with caspase 8 in death-inducing signaling complex (Wang et al. 2004). Furthermore, in skin organ cultures and in in vitro cultured keratinocytes, PV-IgG is shown to be able to induce the caspase activation and DNA fragmentation, and the caspase inhibitors can prevent the formation of PV-IgG-induced epidermal lesions. In support, another independent report showed caspase-3 activation, Bcl-2 depletion, and Bax expression, and the p38 MAPK inhibitors were able to block the activation of caspase-3, the proapoptotic proteinase, suggesting that initiation of apoptosis is downstream to, and a consequence of, p38MAPK activation (Lee et al. 2009a). Hence, the Fas-mediated cell death seems to be involved in PV-IgG signaling and ultimately the pemphigus acantholysis.

Later studies suggest that the activation of EGFR, followed by its internalization, is instrumental in PV-IgG induced p38 MAPK signaling and apoptotic pathway (Bektas et al. 2013; Frusic-Zlotkin et al. 2006; Grando et al. 2009) (Fig. 3). Keratinocytes stimulated with PV-IgG exhibited activation and autophosphorylation of EGFR and its downstream signaling via ERK/c-Jun. Inhibition with the specific tyrosine kinase inhibitor AG1478 abrogated the EGFR autophosphorylation, cell death, FasL appearance, and acantholysis (Frusic-Zlotkin et al. 2006). Concomitantly, EGFR inhibition also prevented PV-IgG-induced Dsg3 internalization and keratin intermediate filament retraction (Bektas et al. 2013). Importantly, this finding has been verified in both neonatal and adult mouse models by independent groups. In the passive transfer neonatal model of pemphigus, EGFR inhibition showed prevention of PV-IgG-induced blister formation and skin lesion (Bektas et al. 2013). In an adult mouse model with passive transfer of pathogenic AK23 that specifically targets Dsg3, Müller and colleagues demonstrated that 2 h after AK23 transfer, detachment of desmosomes and activation of EGFR occurred, and this was followed by several events such as the increased c-Myc expression, epidermal hyper-proliferation, Dsg3 depletion, and blister formation in oral mucous membrane and hair follicles (Schulze et al. 2012). Furthermore, an imbalance in Akt/mTOR (with almost lack of activated Akt and high levels of activated mTOR) was detected in basal epidermal keratinocytes in passive transfer model, suggesting the imbalance in Akt/mTOR could be involved in the development of apoptosis and acantholysis downstream of EGFR (Pretel et al. 2009). In line with these findings, another report indicated enhanced FAK phosphorylation on Tyr397/925 in the basal layer of epidermis in passive transfer model and inhibition of FAK reduced the expression of phosphorylated Src and mTOR in the epidermis (Gil et al. 2012). When mouse was pretreated with the specific FAK inhibitor, the acantholysis was disappeared. What is more, when inhibitors for HER isoforms, Src, mTOR, and pan-caspases were employed together before PV-IgG administration, the phosphorylated FAK (Y397/925) was decreased, suggesting that likely there is a positive feedback loop in PV-IgG-induced signaling. Besides, pretreatment with the FAK inhibitor also showed to prevent alterations in the Bax and Bcl-2 expression and caspase-9/caspase-3 activities induced by PV-IgG.
Desmoglein-3, Fig. 3

Dsg3 cross talks with EGFR. PV-IgG binding to Dsg3 triggers the EGFR signaling in keratinocytes that involves p38, Src, and ERK pathways and ultimately elicit activation of the transcription factors c-Myc and c-Jun/AP-1, leading to enhanced cell proliferation, apoptosis, and cell–cell detachment

Plakoglobin (Pg), a binding partner of Dsg3 and with dual functions in both desmosomes and nucleus, plays a role in suppression of transcription factor c-Myc and is described as the principle effecter of PV-IgG-mediated signals downstream of c-Myc (Williamson et al. 2006; Williamson et al. 2007; de Bruin et al. 2007). When keratinocytes treated by PV-IgG, the nonjunctional pool of Dsg3 along with Pg undergoes a process of enhanced protein turnover leading to depletion of nuclear Pg and attenuation of its suppression of c-Myc (Fig. 3). As a consequence, a marked increase in c-Myc accumulation and proliferating Ki67-positive cells was presented in PV of both human and animal patients. In line with this finding, Pg-knockout mouse exhibited high levels of c-Myc in epidermal keratinocytes, further confirming a suppressive role of Pg in c-Myc activity. What is more, another desmosomal adaptor protein plakophilins 3 (Pkp3) is implicated as an effecter of Src signaling, and upon PV-IgG binding to keratinocytes and activation of Src, tyrosine phosphorylation of Pkp3 was induced leading to the detachment of Pkp3 from Dsg3 and cytoplasmic accumulation accompanied with cell dissociation (Cirillo et al. 2014). Taken together, all these data support the notion that Dsg3 cross talks with EGFR and regulates its signaling pathway, including the downstream effecters Src, ERK, p38 MAPK, and c-Jun as well as the desmosomal adaptor proteins Pg and Pkp3 that collectively result in gross effects on cell proliferation, apoptosis, as well as cell–cell detachment.

Although strong evidence suggests activation of EGFR is necessary for PV-IgG-induced apoptosis and cell–cell detachment, there is also reports, however, arguing against this theory with the findings implying that PV-IgG-mediated signaling does not require EGFR and its internalization, especially the phosphorylation at Tyrosine (Tyr)-1173 (the canonical activation of EGFR) and the c-Src-dependent site Tyr-845, nor apoptosis as absence of apoptosis was observed in the early lesions of PV acantholysis in vivo and also in the keratinocyte cultures treated with PV-IgG in vitro (Heupel et al. 2009; Schmidt and Waschke 2009; Schmidt et al. 2009). Even if both PV-IgG and EGF elicit cell discohesion and cytokeratin retraction, only the effects of EGF can be blocked by inhibition of EGFR and c-Src. In support, laser tweezer experiments showed that impaired bead binding of Dsg3 and Dsg1 in response to PV-IgG was not affected by inhibition of either EGFR or c-Src. These findings implicate that neither EGFR nor Src attributes to the loss of Dsg-mediated adhesion, cytokeratin retraction, and keratinocyte dissociation and suggest that apoptosis detected in PV may occur secondary to acantholysis event.

Signaling to E-Cadherin/Src and the Wnt/Beta-Catenin Pathways

Src family of nonreceptor tyrosine kinases plays a positive role in control of junction assembly and cell adhesion through a mechanism of regulating tyrosine phosphorylation of adherens junction and desmosomal proteins, including E-cadherin and Dsg3, in differentiating keratinocytes (Calautti et al. 1998; Rotzer et al. 2015; Tsang et al. 2010; Tsang et al. 2012b). Accompanied with protein phosphorylation, the formation of E-cadherin complex and its mediated cell cohesion is enhanced. Inhibition of tyrosine kinase not only prevents increased association of catenins with E-cadherin but also has a negative impact on the cell adhesive structures resulting in a significant reduction in the adhesive strength of keratinocytes. As described above, activation of Src is found in keratinocytes treated with PV-IgG both in vitro and in vivo, and inhibition of tyrosine kinases has proved to be successful in preventing Dsg3 internalization and PV-IgG-induced disruption of desmosomes and epidermal acantholysis (Delva et al. 2008; Tsang et al. 2012b). Besides, recent studies have revealed that Dsg3 cross talks with E-cadherin and acts as an upstream regulator of E-cadherin/Src signaling (Tsang et al. 2010; Tsang et al. 2012b) (Fig. 4). A complex formation containing Dsg3, E-cadherin, and Src has been demonstrated in a calcium-dependent manner, and overexpression of Dsg3 in epithelial cells elicits an increase of Src and its activity within the E-cadherin complex and knockdown of Dsg3 resulted in an inverse effect on the Src expression levels in the complex. As a consequence, Dsg3 depletion affects not only the E-cadherin junction assembly but also the expression of desmosomal proteins and proper formation of the desmosome junctions, resulting in compromised cell–cell adhesion as observed in pemphigus disease. It is worth noting that overexpression of Dsg3 in cancer cell lines does not necessarily enhance cell cohesion but rather caused accelerated cell migration and invasion due to aberrant activation or hijack of several signaling pathways including Src and its downstream effecters such as tyrosine phosphorylation of adherens junction proteins, leading to lysosomal degradation of proteins including E-cadherin (Tsang et al. 2010). In line with this finding, recently, another independent study has also demonstrated the existence of such a protein complex containing Dsg3, E-cadherin, and Src in keratinocytes and indicates that Src is required for the stability of the complex as well as the association of Dsg3 with cytoskeleton that is required for desmosome assembly (Rotzer et al. 2015). Inhibition of Src by PP1, a potent Src inhibitor, caused a reduction of tyrosine phosphorylation of Dsg3 and E-cadherin and their association with Src in the cytoskeletal fraction. Furthermore, it has been proposed that the Dsg3-mediated Src activation likely involves Cav-1, a scaffolding protein in a special type of lipid raft known as caveolae (Fig. 4), and the overexpression of Dsg3 leads to its competition with the inactive form of Src for binding to Cav-1, thus causing the release of Src followed by its autoactivation (Wan et al. 2016). Cav-1 is known to negatively regulate the Src activity through an inhibitory interaction which prevents its autophosphorylation (Li et al. 1996; Okamoto et al. 1998). Caveolae is thought to modulate signal transduction through the compartmentalization of specific signaling molecules and regulation of their activity (Lisanti et al. 1994). Emerging evidence suggests that both Src and Cav-1 associate with Dsg3 and a modulation of Dsg3 levels (overexpression or knockdown) causes an inverse effect on the amount of Src molecules bound to Cav-1 (Wan et al. 2016). In support, a potential binding site for the scaffolding domain of Cav-1 is identified within the C-terminus of human Dsg3 at amino acids 788–798 that contain four aromatic amino acid residues (Wan et al. 2016), and this region shares some common feature with the characterized amino acid sequence that binds to the scaffolding domain of Cav-1 (Couet et al. 1997). It is worth noting that this region is highly conserved within the desmoglein subfamily members (Dsg1–4) as well as across most of 18 species (Wan et al. 2016).
Desmoglein-3, Fig. 4

Dsg3 forms a complex with and regulates E-cadherin/Src signaling. A nonjunctional pool of Dsg3 that forms a complex with E-cadherin is also found to bind to caveolin-1 (Cav-1). Such an interaction may enable Dsg3 to compete with inactive Src for binding to Cav-1 and thus causes release of Src from its interaction with Cav-1 followed by its autoactivation (Wan et al. 2016). The complex of Dsg3, E-cadherin, and Src, as well as the Src-mediated phosphorylation of cadherins, seems to be required for E-cadherin and desmosome junction formation (Rotzer et al. 2015). Binding and recruitment of Pg by Dsg3 is also necessary for enhancing β-catenin-LEF/TCF interaction and activation (Chen et al. 2013)

Dsg3 is also implicated to play a part in influencing Wnt/beta-catenin signal pathway (Fig. 4). In addition to a cell adhesive role in adherens junctions, beta-catenin is known to act as a transcriptional coregulator in Wnt-signal pathway (Novak and Dedhar 1999; Kikuchi et al. 2006). The conserved Wnt/beta-catenin signaling plays an important role in regulating development, cell proliferation, migration, and cell-fate decision. Activation of this signal pathway stabilizes beta-catenin in the cytoplasm, leading its translocation to the nucleus via Rac1 and other factors, where it binds to LEF/TCF transcription factors and increases the expression of Wnt target genes, such as Myc, cyclin D1, TCF-1, PPAR-δ, MMP-7, Axin-2, and CD44, etc., in order to facilitate cell migration. In the absence of Wnt-signal, beta-catenin is targeted to ubiquitination and proteasomal degradation. In vitro study showed that overexpression of Dsg3 in A431 cancer cell line activates beta-catenin and its transcriptional activity to some degree (unpublished data). In line with this, a recent report suggested that Dsg3 regulates Wnt/β-catenin signaling indirectly, in a Pg-dependent manor, by a mechanism of sequestering Pg and preventing its nuclear translocation and suppression of LEF/TCF transcriptional activity (Chen et al. 2013). Dsg3 deletion caused an inverse effect with increased nucleus translocation where Pg interacts with and inhibits TCF/LEF transcription activity, resulting in suppression of tumor growth and invasion. Correspondingly, the increased levels of Dsg3 were shown to be correlated with reduced nuclear Pg accompanied with the elevated expression of the LEF/TCF transcriptional targets, cyclin D1, c-Myc, and MMP7, in both the head and neck cancer tissues and the cultured oral cancer cell lines (Chen et al. 2013). Thus, upregulation of Dsg3 in squamous cancer could potentially tip the balance in favor of the β-catenin-LEF/TCF interaction and activation via the suppression of the Pg nuclear translocation.

Dsg3 Regulates Rho GTPase, Ezrin, c-Jun/AP-1, and Organization of Actin Cytoskeleton

Since pemphigus is a cell-adhesion disease, it is not surprising that the activity of Rho GTPase and actin cytoskeleton are implicated in PV-IgG signaling and acantholysis. Waschke et al. first reported that the interference of RhoA signaling occurs in both PV- and PF-IgG induce skin blistering as the treatment with bacterial toxins for Rho GTPases (Escherichia coli cytotoxic necrotizing factor 1 (CNF-1) that activates RhoA, Rac1, and Cdc42, and CNFy from Yersinia pseudotuberculosis that selectively activates RhoA) showed to prevent epidermal splitting after 24 h of incubation along with pemphigus-IgG (Waschke et al. 2006). In vitro study based on HaCaT keratinocytes showed a reduction of RhoA activity accompanied with pemphigus-IgG-induced disruption of cell adhesion as well as in the loss of Dsg1-mediated binding probed by laser tweezers, the events found to be dependent on p38 MAPK (Figs. 2, 3, 5). In support, profound alterations of the F-actin distribution, along with the depletion of Dsg3 from the cytoskeleton pool in PV-IgG treated cells, were abolished by treating the cells with CNFy, suggesting that the activity of RhoA is required for desmosomal adhesion, stability, and homeostasis. In line with this study, the same group has demonstrated that PV-IgG has an influence on actin dynamics (Gliem et al. 2010). Using various pharmacological agents, they showed that manipulation of actin polymerization is able to modulate the pathogenic effects of PV-IgG. For instance, jasplakinolide that stabilizes actin filaments significantly blocked cell discohesion, whereas cytochalasin D that disrupts the polymerization of actin filaments caused augmented pathogenic effects of PV-IgG. It was also shown that the CNF-1-mediated activation of Rho-GTPases enhanced the cortical actin belt and blunted PV-IgG-induced cell dissociation. However, when actin polymerization was blocked under these conditions via addition of latrunculin B, the protective effects of CNF-1 were abolished. Taken together, all these findings underscore that reorganization of cortical actin is involved in PV-IgG-induced keratinocyte dissociation and epidermal acantholysis.
Desmoglein-3, Fig. 5

The PV-IgG targeted activation of p38 MAPK inhibits the activity of RhoA. On the other hand, overexpression of Dsg3 (gain-of-function) activates Rac1/Cdc42 GTPases, leading to the activation of PKC/Ezrin pathway and also c-Jun/AP-1 in PKC-dependent manner, that in turn regulates actin organization and dynamics with a gross effect on cell adhesion, morphology, and motility.

In vitro study using gain-of-function approach showed that overexpression of full-length human Dsg3 in epithelial cells causes remarkable induction of Rac1/Cdc42 and to a lesser extent, RhoA (Tsang et al. 2012a). Such an activation of Rho GTPases is accompanied with significant increase of actin turnover and pronounced membrane protrusions and dynamics in various epithelial cell lines, including MDCK and A431 epidermoid cells (Tsang et al. 2012a). As a consequence, enhanced cell migration and invasion is consistently observed in these cells when compared to the respective control cells with relatively low levels of endogenous Dsg3 expression. Knockdown of Dsg3 results in perturbation in junction formation and accompanied cell polarization that require cortical actin assembly. Using various techniques, such as immunofluorescence, biochemical methods, as well as mass spectrometry, it was shown that Dsg3 not only colocalizes with but also physically interacts with actin proteins although the actual nature of their association remains undefined (Tsang et al. 2012a; Brown et al. 2014). In line with this finding, it is not surprising that Dsg3 is found to interact with an actin binding protein Ezrin, a member of the ERM family. Partial colocalization between Dsg3 and Ezrin is displayed at the plasma membrane, especially in the membrane projections of A431 cells. Furthermore, this interaction is proved by coimmunoprecipitation analysis with the rabbit anti-Ezrin antibody in Dsg3-dosage-dependent manner (Brown et al. 2014). In addition, Dsg3 is found to be capable of regulating the Ezrin activation by enhancing phosphorylation at Thre567 residual which is known to attribute to the accelerated motility of cancer cells. The functional importance of such an interaction was further validated by colocalization analysis of Ezrin/F-actin or CD44/F-actin at the plasma membrane that suggests that Dsg3 is required for the proper function of Ezrin at the plasma membrane since Dsg3 knockdown impaired the associations between these proteins (Brown et al. 2014). The increased expression and activation of Ezrin is known to have positive correlation with cancer development, progression, and metastasis (Kong et al. 2013; Clucas and Valderrama 2014). The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by inhibition of PKC, p38 MAPK, Rho kinases that are known to be involved in Ezrin activation (Brown et al. 2014) (Fig. 5). This finding indicates that Ezrin is likely a downstream effecter of Dsg3 signaling that regulates cortical actin organization as well as junction assembly. What is more, activation of c-Jun/AP-1 has also been identified in Dsg3-overexpressing cells by phospho-kinase array analysis and the luciferase activity assay in various cell lines with a marked increase in c-Jun S63 phosphorylation (Brown et al. 2014) (unpublished data) (Fig. 5). Knockdown of Dsg3 in A431 cell line showed more than twofold reduction of AP-1 activity relative to the matched control cells, assessed by the luciferase activity assay. Altogether, these additional data place Dsg3 as a key surface regulator for PKC-dependent Ezrin phosphorylation (activation) as well as the c-Jun/AP-1 activation that likely contributes to its procancerous role in Dsg3 associated cancer progression and metastasis.


Although Dsg3 was originally described as a desmosomal adhesion protein, accumulating evidence suggests that it is a versatile molecule with its role more related to cell signaling in epithelial cells. It is worth noting that Dsg3 is not only found in the core domain of desmosomes but also recognized to be distributed on the entire surface at the plasma membrane, and thus its signaling roles as described above are likely associated with its nonjunctional pool beyond the desmosome adhesion. In fact, the protein complex containing Dsg3 and other signal molecules such as Src and Ezrin is detectable in nonionic detergent soluble fraction that is disassociated with the cytoskeleton. Of interest, when expressing chimeric construct that encodes the extracellular domain of Dsg3 and the cytoplasmic domain of E-cadherin in fibroblast L-cells, they only displayed slight aggregation in contrast to that transfected with the wild type of E-cadherin (Amagai et al. 1994). In line with this finding, overexpression of wild-type Dsg3 in epithelial cell lines failed to render enhanced cell–cell adhesion but instead showed promoted cell migration and invasion accompanied with the downregulation of E-cadherin adhesion due to the activation of Src and other signaling pathways (Brown et al. 2014; Tsang et al. 2010).

Dsg3 is found to be associated with two human diseases, PV and squamous cell carcinoma. As a major target of PV-IgGs, Dsg3 is able to trigger a cascade of intracellular events, including the phosphorylation of itself and its depletion from the desmosomes and cell surface and concomitant activation of various signal molecules, such as PLC, PKC, EGFR, Src, p38 MAPK, and c-Myc. As a consequence, cell–cell detachment occurs, leading to blistering and pemphigus acantholysis in Dsg3 baring tissues such as skin and oral mucosa. Disruption of cell cohesion is also accompanied with changes in cell proliferation and induction of apoptosis due to the activation of c-Myc and p38 MAPK pathways, respectively, that attribute to pemphigus acantholysis. On the other hand, upregulation of Dsg3 is found in squamous cell carcinoma in various organs and shows a positive correlation with clinical grade and poor differentiation of cancers. In support, in vitro studies have demonstrated that overexpression of Dsg3 in cancer cell lines (gain-of-function) elicits activation of signal pathways, including Src, Rac1/Cdc42 GTPases, Ezrin, as well as transcription factors c-Jun/AP-1, all of which are known to be responsible for cancer invasion and metastasis. Thus, deregulation of Dsg3 signaling may play a key part in cancer development and progression. However, our current understanding of the biological function of Dsg3 and its related cellular and molecular mechanisms remains limited, and there are still many questions unanswered. For instance, we still do not understand why the distinct expression patterns of Dsg3 exist in epidermis and oral mucous membrane, both of which are the stratified squamous epithelia, with more restricted basal distribution in the former and broad uniform expression in the latter. Is there any specific function for Dsg3 that is correlated to such a distinct tissue distribution? What is the actual ligand or environmental cue that triggers the Dsg3 signaling? Does it exert a function in response to tissue mechanics as many of the pathways regulated by Dsg3 are known to be involved in mechanotransduction? Can Dsg3 serve as a drug target in cancer therapy? Of course, it is challenging to address all these questions. Future investigation will advance our knowledge and shed light on the additional role of Dsg3 in cell biology.


  1. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991;67(5):869–87.PubMedCrossRefGoogle Scholar
  2. Amagai M, Karpati S, Klaus-Kovtun V, Udey MC, Stanley JR. Extracellular domain of pemphigus vulgaris antigen (desmoglein 3) mediates weak homophilic adhesion. J Invest Dermatol. 1994;103(4):609–15.PubMedCrossRefGoogle Scholar
  3. Andl CD, Stanley JR. Central role of the plakoglobin-binding domain for desmoglein 3 incorporation into desmosomes. J Invest Dermatol. 2001;117(5):1068–74.PubMedCrossRefGoogle Scholar
  4. Aoyama Y, Owada MK, Kitajima Y. A pathogenic autoantibody, pemphigus vulgaris-IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol. 1999;29(7):2233–40.PubMedCrossRefGoogle Scholar
  5. Bektas M, Jolly PS, Berkowitz P, Amagai M, Rubenstein DS. A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis. J Biol Chem. 2013;288(13):9447–56.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Berkowitz P, Hu P, Liu Z, Diaz LA, Enghild JJ, Chua MP, Rubenstein DS. Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem. 2005;280(25):23778–84.PubMedCrossRefGoogle Scholar
  7. Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubenstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci USA. 2006;103(34):12855–60.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Berkowitz P, Chua M, Liu Z, Diaz LA, Rubenstein DS. Autoantibodies in the autoimmune disease pemphigus foliaceus induce blistering via p38 mitogen-activated protein kinase-dependent signaling in the skin. Am J Pathol. 2008a;173(6):1628–36.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Berkowitz P, Diaz LA, Hall RP, Rubenstein DS. Induction of p38MAPK and HSP27 phosphorylation in pemphigus patient skin. J Invest Dermatol. 2008b;128(3):738–40.PubMedCrossRefGoogle Scholar
  10. Brown L, Wan H. Desmoglein 3: a help or a hindrance in cancer progression? Cancers (Basel). 2015;7(1):266–86.CrossRefGoogle Scholar
  11. Brown L, Waseem A, Cruz IN, Szary J, Gunic E, Mannan T, Unadkat M, Yang M, Valderrama F, O’Toole EA, Wan H. Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation. Oncogene. 2014;33(18):2363–74.PubMedCrossRefGoogle Scholar
  12. Calautti E, Cabodi S, Stein PL, Hatzfeld M, Kedersha N, Paolo DG. Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion. J Cell Biol. 1998;141(6):1449–65.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Chen YJ, Lee LY, Chao YK, Chang JT, Lu YC, Li HF, Chiu CC, Li YC, Li YL, Chiou JF, Cheng AJ. DSG3 facilitates cancer cell growth and invasion through the DSG3-plakoglobin-TCF/LEF-Myc/cyclin D1/MMP signaling pathway. PLoS One. 2013;8(5):e64088.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chernyavsky AI, Arredondo J, Kitajima Y, Sato-Nagai M, Grando SA. Desmoglein versus non-desmoglein signaling in pemphigus acantholysis: characterization of novel signaling pathways downstream of pemphigus vulgaris antigens. J Biol Chem. 2007;282(18):13804–12.PubMedCrossRefGoogle Scholar
  15. Cirillo N, AlShwaimi E, McCullough M, Prime SS. Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3. Autoimmunity. 2014;47(2):134–40.PubMedCrossRefGoogle Scholar
  16. Clucas J, Valderrama F. ERM proteins in cancer progression. J Cell Sci. 2014;127(Pt 2):267–75.PubMedCrossRefGoogle Scholar
  17. Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP. Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem. 1997;272(10):6525–33.PubMedCrossRefGoogle Scholar
  18. Davisson MT, Cook SA, Johnson KR, Eicher EM. Balding: a new mutation on mouse chromosome 18 causing hair loss and immunological defects. J Hered. 1994;85(2):134–6.PubMedCrossRefGoogle Scholar
  19. de Bruin A, Caldelari R, Williamson L, Suter MM, Hunziker T, Wyder M, Muller EJ. Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris. Exp Dermatol. 2007;16(6):468–75.PubMedCrossRefGoogle Scholar
  20. Delva E, Jennings JM, Calkins CC, Kottke MD, Faundez V, Kowalczyk AP. Pemphigus vulgaris IgG-induced desmoglein-3 endocytosis and desmosomal disassembly are mediated by a clathrin- and dynamin-independent mechanism. J Biol Chem. 2008;283(26):18303–13.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Esaki C, Seishima M, Yamada T, Osada K, Kitajima Y. Pharmacologic evidence for involvement of phospholipase C in pemphigus IgG-induced inositol 1,4,5-trisphosphate generation, intracellular calcium increase, and plasminogen activator secretion in DJM-1 cells, a squamous cell carcinoma line. J Invest Dermatol. 1995;105(3):329–33.PubMedCrossRefGoogle Scholar
  22. Frank J, Cserhalmi-Friedman PB, Ahmad W, Panteleyev AA, Aita VM, Christiano AM. Characterization of the desmosomal cadherin gene family: genomic organization of two desmoglein genes on human chromosome 18q12. Exp Dermatol. 2001;10(2):90–4.PubMedCrossRefGoogle Scholar
  23. Frusic-Zlotkin M, Raichenberg D, Wang X, David M, Michel B, Milner Y. Apoptotic mechanism in pemphigus autoimmunoglobulins-induced acantholysis – possible involvement of the EGF receptor. Autoimmunity. 2006;39(7):563–75.PubMedCrossRefGoogle Scholar
  24. Gil MP, Modol T, Espana A, Lopez-Zabalza MJ. Inhibition of FAK prevents blister formation in the neonatal mouse model of pemphigus vulgaris. Exp Dermatol. 2012;21(4):254–9.PubMedCrossRefGoogle Scholar
  25. Gliem M, Heupel WM, Spindler V, Harms GS, Waschke J. Actin reorganization contributes to loss of cell adhesion in pemphigus vulgaris. Am J Physiol Cell Physiol. 2010;299(3):C606–13.PubMedCrossRefGoogle Scholar
  26. Grando SA, Bystryn JC, Chernyavsky AI, Frusic-Zlotkin M, Gniadecki R, Lotti R, Milner Y, Pittelkow MR, Pincelli C. Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis. Exp Dermatol. 2009;18(9):764–70.PubMedCrossRefGoogle Scholar
  27. Heupel WM, Engerer P, Schmidt E, Waschke J. Pemphigus vulgaris IgG cause loss of desmoglein-mediated adhesion and keratinocyte dissociation independent of epidermal growth factor receptor. Am J Pathol. 2009;174(2):475–85.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Jolly PS, Berkowitz P, Bektas M, Lee HE, Chua M, Diaz LA, Rubenstein DS. p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis. J Biol Chem. 2010;285(12):8936–41.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Kanno M, Isa Y, Aoyama Y, Yamamoto Y, Nagai M, Ozawa M, Kitajima Y. P120-catenin is a novel desmoglein 3 interacting partner: identification of the p120-catenin association site of desmoglein 3. Exp Cell Res. 2008;314(8):1683–92.PubMedCrossRefGoogle Scholar
  30. Kawasaki Y, Aoyama Y, Tsunoda K, Amagai M, Kitajima Y. Pathogenic monoclonal antibody against desmoglein 3 augments desmoglein 3 and p38 MAPK phosphorylation in human squamous carcinoma cell line. Autoimmunity. 2006;39(7):587–90.PubMedCrossRefGoogle Scholar
  31. Kikuchi A, Kishida S, Yamamoto H. Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. Exp Mol Med. 2006;38(1):1–10.PubMedCrossRefGoogle Scholar
  32. Kitajima Y. 150(th) anniversary series: desmosomes and autoimmune disease, perspective of dynamic desmosome remodeling and its impairments in pemphigus. Cell Commun Adhes. 2014;21(6):269–80.PubMedCrossRefGoogle Scholar
  33. Kitajima Y, Aoyama Y, Seishima M. Transmembrane signaling for adhesive regulation of desmosomes and hemidesmosomes, and for cell-cell datachment induced by pemphigus IgG in cultured keratinocytes: involvement of protein kinase C. J Investig Dermatol Symp Proc. 1999;4(2):137–44.PubMedCrossRefGoogle Scholar
  34. Koch PJ, Mahoney MG, Ishikawa H, Pulkkinen L, Uitto J, Shultz L, Murphy GF, Whitaker-Menezes D, Stanley JR. Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol. 1997;137(5):1091–102.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Koch PJ, Mahoney MG, Cotsarelis G, Rothenberger K, Lavker RM, Stanley JR. Desmoglein 3 anchors telogen hair in the follicle. J Cell Sci. 1998;111(Pt 17):2529–37.PubMedGoogle Scholar
  36. Kong J, Li Y, Liu S, Jin H, Shang Y, Quan C, Li Y, Lin Z. High expression of ezrin predicts poor prognosis in uterine cervical cancer. BMC Cancer. 2013;13:520.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Kountikov EI, Poe JC, Maclver NJ, Rathmell JC, Tedder TF. A spontaneous deletion within the desmoglein 3 extracellular domain of mice results in hypomorphic protein expression, immunodeficiency, and a wasting disease phenotype. Am J Pathol. 2015;185(3):617–30.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Lee HE, Berkowitz P, Jolly PS, Diaz LA, Chua MP, Rubenstein DS. Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis. J Biol Chem. 2009a;284(18):12524–32.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Lee JS, Yoon HK, Sohn KC, Back SJ, Kee SH, Seo YJ, Park JK, Kim CD, Lee JH. Expression of N-terminal truncated desmoglein 3 (deltaNDg3) in epidermis and its role in keratinocyte differentiation. Exp Mol Med. 2009b;41(1):42–50.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Li S, Couet J, Lisanti MP. Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem. 1996;271(46):29182–90.PubMedCrossRefGoogle Scholar
  41. Lisanti MP, Scherer PE, Tang Z, Sargiacomo M. Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol. 1994;4(7):231–5.PubMedCrossRefGoogle Scholar
  42. Mao X, Sano Y, Park JM, Payne AS. p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J Biol Chem. 2011;286(2):1283–91.PubMedCrossRefGoogle Scholar
  43. Mao X, Li H, Sano Y, Gaestel M, Mo PJ, Payne AS. MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol. 2014;134(1):68–76.PubMedCrossRefGoogle Scholar
  44. Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf. Cell Mol Life Sci. 1999;56(5–6):523–37.PubMedCrossRefGoogle Scholar
  45. Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem. 1998;273(10):5419–22.PubMedCrossRefGoogle Scholar
  46. Osada K, Seishima M, Kitajima Y. Pemphigus IgG activates and translocates protein kinase C from the cytosol to the particulate/cytoskeleton fractions in human keratinocytes. J Invest Dermatol. 1997;108(4):482–7.PubMedCrossRefGoogle Scholar
  47. Pelacho B, Natal C, Espana A, Sanchez-Carpintero I, Iraburu MJ, Lopez-Zabalza MJ. Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes. FEBS Lett. 2004;566(1–3):6–10.PubMedCrossRefGoogle Scholar
  48. Pretel M, Espana A, Marquina M, Pelacho B, Lopez-Picazo JM, Lopez-Zabalza MJ. An imbalance in Akt/mTOR is involved in the apoptotic and acantholytic processes in a mouse model of pemphigus vulgaris. Exp Dermatol. 2009;18(9):771–80.PubMedCrossRefGoogle Scholar
  49. Pulkkinen L, Choi YW, Simpson A, Montagutelli X, Sundberg J, Uitto J, Mahoney MG. Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene. J Invest Dermatol. 2002;119(6):1237–43.PubMedCrossRefGoogle Scholar
  50. Rotzer V, Hartlieb E, Vielmuth F, Gliem M, Spindler V, Waschke J. E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion. Cell Mol Life Sci. 2015;72(24):4885–97.PubMedCrossRefGoogle Scholar
  51. Saito M, Stahley SN, Caughman CY, Mao X, Tucker DK, Payne AS, Amagai M, Kowalczyk AP. Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation. PLoS One. 2012;7(12):e50696.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Schmidt E, Waschke J. Apoptosis in pemphigus. Autoimmun Rev. 2009;8(7):533–7.PubMedCrossRefGoogle Scholar
  53. Schmidt E, Gutberlet J, Siegmund D, Berg D, Wajant H, Waschke J. Apoptosis is not required for acantholysis in pemphigus vulgaris. Am J Physiol Cell Physiol. 2009;296(1):C162–72.PubMedCrossRefGoogle Scholar
  54. Schulze K, Galichet A, Sayar BS, Scothern A, Howald D, Zymann H, Siffert M, Zenhausern D, Bolli R, Koch PJ, Garrod D, Suter MM, Muller EJ. An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris. J Invest Dermatol. 2012;132(2):346–55.PubMedCrossRefGoogle Scholar
  55. Seishima M, Esaki C, Osada K, Mori S, Hashimoto T, Kitajima Y. Pemphigus IgG, but not bullous pemphigoid IgG, causes a transient increase in intracellular calcium and inositol 1,4,5-triphosphate in DJM-1 cells, a squamous cell carcinoma line. J Invest Dermatol. 1995;104(1):33–7.PubMedCrossRefGoogle Scholar
  56. Spindler V, Endlich A, Hartlieb E, Vielmuth F, Schmidt E, Waschke J. The extent of desmoglein 3 depletion in pemphigus vulgaris is dependent on Ca(2+)-induced differentiation: a role in suprabasal epidermal skin splitting? Am J Pathol. 2011;179(4):1905–16.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Thomason HA, Scothern A, McHarg S, Garrod DR. Desmosomes: adhesive strength and signalling in health and disease. Biochem J. 2010;429(3):419–33.PubMedCrossRefGoogle Scholar
  58. Tsang SM, Liu L, Teh MT, Wheeler A, Grose R, Hart IR, Garrod DR, Fortune F, Wan H. Desmoglein 3, via an interaction with E-cadherin, is associated with activation of Src. PLoS One. 2010;5(12):e14211.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Tsang SM, Brown L, Gadmor H, Gammon L, Fortune F, Wheeler A, Wan H. Desmoglein 3 acting as an upstream regulator of Rho GTPases, Rac-1/Cdc42 in the regulation of actin organisation and dynamics. Exp Cell Res. 2012a;318(18):2269–83.PubMedCrossRefGoogle Scholar
  60. Tsang SM, Brown L, Lin K, Liu L, Piper K, O’Toole EA, Grose R, Hart IR, Garrod DR, Fortune F, Wan H. Non-junctional human desmoglein 3 acts as an upstream regulator of Src in E-cadherin adhesion, a pathway possibly involved in the pathogenesis of pemphigus vulgaris. J Pathol. 2012b;227(1):81–93.PubMedCrossRefGoogle Scholar
  61. Vielmuth F, Waschke J, Spindler V. Loss of desmoglein binding is not sufficient for keratinocyte dissociation in pemphigus. J Invest Dermatol. 2015;135(12):3068–77.PubMedCrossRefGoogle Scholar
  62. Wan H, Lin K, Tsang SM, Uttagomol J. Evidence for Dsg3 in regulating Src signaling by competing with it for binding to caveolin-1. Data Brief. 2016;6:124–34.PubMedCrossRefGoogle Scholar
  63. Wang X, Bregegere F, Frusic-Zlotkin M, Feinmesser M, Michel B, Milner Y. Possible apoptotic mechanism in epidermal cell acantholysis induced by pemphigus vulgaris autoimmunoglobulins. Apoptosis. 2004;9(2):131–43.PubMedCrossRefGoogle Scholar
  64. Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G, Drenckhahn D. Inhibition of Rho A activity causes pemphigus skin blistering. J Cell Biol. 2006;175(5):721–7.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Williamson L, Raess NA, Caldelari R, Zakher A, de Bruin A, Posthaus H, Bolli R, Hunziker T, Suter MM, Muller EJ. Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J. 2006;25(14):3298–309.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Williamson L, Suter MM, Olivry T, Wyder M, Muller EJ. Upregulation of c-Myc may contribute to the pathogenesis of canine pemphigus vulgaris. Vet Dermatol. 2007;18(1):12–7.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK