So far, the interplay between transcription factor networks and context-dependent stimuli that control desmosome gene transcription and isotype expression remain incompletely understood. In the epidermis, differential expression and/or activity of transcription factors would be expected to regulate the differentiation-dependent expression of genes including desmosomal genes. Several transcription factors are known to control stratification and barrier formation. The transcription factor tumor protein 63 (Tp63) is necessary for both, epidermal stem cell self-renewal and differentiation, whereas CCAAT/enhancer-binding protein (C/EBP) α/β, Kruppel-like factor (KLF) 4, and grainyhead-like (GRHL) 3 promote differentiation (Segre et al., 1999; Ting et al., 2005; Truong et al., 2006; Senoo et al., 2007; Lopez et al., 2009; Sen et al., 2012). Tp63 regulates a subset of desmosomal genes including DSG1, DSC3, and DSP which were significantly reduced by mutant Tp63. Chromatin immunoprecipitation (ChIP) and transactivation assays indicated that Tp63 directly controls the transcription of these genes (Ferone et al., 2013).

Aiming to understand the processes underlying the differential expression of DSC genes in the epidermis, Smith et al. (2004) isolated the DSC1 and DSC3 5′-flanking DNA regions and analyzed their activity in primary keratinocytes. They found differential regulation of DSC genes by C/EBP family members: C/EBPα activated DSC1 expression while C/EBPβ promoted DSC3 expression. In contrast, C/EBPδ supported the expression of both DSC genes. Analysis of the upstream sequences of DSG genes revealed GC-rich regions and consensus binding sites for transcription factors activator protein 1 and 2 (AP-1, AP-2) (Adams et al., 1998). Given that AP-1 is regulated by growth factor signaling via mitogen-activated protein (MAP) kinases, by serum response factor (SRF) and by mechanical stimuli (Kim et al., 2018; Yeung et al., 2018), it is well-suited to adapt desmosome composition and adhesive function to environmental cues.

KLF4 is essential for barrier acquisition in agreement with its high expression in the differentiating layers of the epidermis (Segre et al., 1999). KLF4 upregulated the expression of the desmosomal proteins DSP, DSG1a, and DSG1b (Swamynathan et al., 2011), whereas KLF5 expression was shown to correlate with DSG2 transcript levels in colon cells (Liu et al., 2017). Another factor that participated in the maintenance of the skin barrier is the transcription factor GRHL1. GRHL1 regulated the expression of DSG1 in suprabasal layers of the epidermis (Mlacki et al., 2014). GRHL1−binding sites were detected in the proximal DSG1 promoters, whereas no such consensus sites were found in the basally expressed DSG2 and DSG3 genes, or in any of the DSC genes. These data suggest that KLF4 and GRHL1 are involved in the differentiation-dependent activation of suprabasal DSG1 transcription. GRHL3-deficient mice exhibited a defective skin barrier and wound repair. Desmosomal genes were not described as direct targets although their expression may be modulated by the GRHL3 targeted transcription factors KLF4, OVO-like transcriptional repressor 1 and OVO-like zinc finger 2 (OVOL1, OVOL2) (Ting et al., 2005; Boglev et al., 2011; Gordon et al., 2014).

Several additional transcription factors have been shown to modulate desmosomal gene expression. These include among others the epithelial to mesenchymal transition associated transcription factors zinc finger E-box binding homeobox 1 and 2 (ZEB1, ZEB2) as well as snail family transcriptional repressor 1 and 2 (SNAI1, SNAI2) which repressed DSG2, DSG3, DSC2, PG, DSP and PKP1, PKP2, and PKP3 expression. Moreover, mechanical forces act through the actin cytoskeleton to regulate the Hippo and SRF pathways, which both affect desmosomal gene expression. ChIP sequencing identified DSG1, DSC1-3, DSP, PKP1, PKP2, and PG as putative targets of the Hippo effectors TEA domain (TEAD) transcription factors (Liu et al., 2016). Actin regulates SRF activity by inhibiting its transcriptional coactivator myocardin-related transcription factor (MRTF). An actin/MRTF/SRF regulatory axis promoted PKP2 gene expression (Leitner et al., 2011).

In summary, several transcription factors with specificity for distinct desmosomal genes have been identified in recent years. However, further studies are required to understand how the activity of these transcriptional regulators is coordinated to ensure spatiotemporal expression of desmosomal genes during epidermal differentiation.

While much of the differential gene expression is achieved at the level of transcription, the contribution of posttranscriptional events to cell-specific expression patterns has recently come into focus. For example, the coordinate synthesis of functionally related proteins can be achieved at the posttranscriptional level by the action of common regulatory molecules, such as RNA binding proteins (RBPs) and non-coding RNAs (ncRNA) (Zanzoni et al., 2019). 3′-untranslated regions (3′-UTR) are known to regulate diverse fates of mRNAs, including degradation, translation, and localization. However, although most of the desmosomal genes contain long 3′-UTRs, little is known about their posttranscriptional regulation.

Posttranslational modifications (PTM) of proteins are crucial for controlling protein stability, localization, and protein interactions and play a key role in numerous biological processes. Reversible modifications include methylation, acetylation, palmitoylation, sumoylation, ubiquitylation, and phosphorylation of specific amino acid side chains. Such modifications coordinately exert dynamic control over protein function in diverse biological contexts. Desmosomal proteins and especially the desmosomal plaque proteins are highly modified by phosphorylation, which in turn is regulated by signaling cascades that are activated by growth factors, mechanical signals or cytokines (summarized in Figure 1). Here, we will focus on the roles of epidermal growth factor receptor (EGFR), insulin like growth factor 1 (IGF1) receptor (IGF1R), and Hippo signaling pathways in controlling desmosome function.

Numerous studies indicate the differential involvement of desmosomal cadherins in the control of proliferation via EGFR signaling (see Figure 2). DSG1 whose expression is restricted to suprabasal keratinocytes, is not only required for maintaining epidermal integrity but also supports keratinocyte differentiation in a desmosome-independent manner. DSG1 facilitated keratinocyte progression to terminal differentiation by suppressing EGFR signaling (Getsios et al., 2009). This was mediated by a DSG1/Erbin/SHOC2 complex, which prevented SHOC2-dependent association of ERK with its activators RAS/RAF, thus attenuating ERK activity and driving differentiation (Harmon et al., 2013). Desmosomes also act as a scaffold to place the constitutive photomorphogenesis 9 (COP9) signalosome close to the EGFR. DSG1 and DSP interacted with the COPS3 subunit of the COP9 signalosome. Since loss of COPS3 as well as DSG1 increased EGFR phosphorylation and compromised keratinocyte differentiation, the authors suggested that DSG1 inhibited EGFR signaling and promoted differentiation in a COP9 signalosome-dependent manner. The molecular mechanism comprised de-neddylation of the EGFR by the COP9 signalosome which triggered ubiquitination and EGFR removal from the cell surface and finally its degradation. This dampened EGFR signaling and consequently cell division, and allowed differentiation to proceed. These data support a model where DSG1-dependent scaffolding of the COP9 signalosome facilitates epidermal differentiation by controlling EGFR dynamics (Najor et al., 2017).

While DSG1 promoted differentiation, the general knockout of DSG2 was associated with embryonic lethality short after implantation, and decreased embryonic stem cell proliferation (Eshkind et al., 2002) suggesting a positive role in the regulation of proliferation. In pluripotent stem cells, DSG2 was essential for self-renewal and suppression of differentiation (Park et al., 2018). Overexpression of DSG2 in basal keratinocytes under the control of the keratin (KRT) 14 promoter did not affect proliferation in general but promoted wound healing associated with elevated EGFR/MAPK activity (Cooper et al., 2018). However, ectopic expression of DSG2 in suprabasal keratinocytes under the control of the involucrin (IVL) promoter activated EGFR signaling and downstream pathways, converging in elevated proliferation and epidermal hyperplasia (Brennan et al., 2007). Thus, ectopic expression of DSG2, which is normally restricted to basal keratinocytes, was sufficient to increase proliferation in suprabasal cells. In agreement with a positive role in growth control, elevated DSG2 levels were observed in several cancers where DSG2 promoted proliferation (Cai et al., 2017; Han et al., 2018; Qin et al., 2020; Sun et al., 2020). Loss of DSG2 suppressed colon cancer cell proliferation through inhibition of EGFR signaling (Kamekura et al., 2014). DSG2 was not only overexpressed and colocalized with EGFR in cutaneous SCCs in vivo, but also promoted Src-mediated EGFR activation required for proliferation and migration in HaCaT and A431 cells (Overmiller et al., 2016). Such an extradesmosomal function of DSG2 in regulating proliferation and migration through activation of EGFR/MAPK pathway was confirmed in cervical cancer and lung adenocarcinoma cell lines (Jin et al., 2020; Zhou and Li, 2020).

DSG3 is most abundant in basal proliferating keratinocytes. Its ectopic expression in suprabasal keratinocytes under the control of the KRT1 promoter led to hyperproliferation and interfered with epidermal differentiation. Cells expressing the proliferation marker Ki-67 were not restricted to the basal layer as in wild type skin but also found in the suprabasal layer (Merritt et al., 2002). A transgenic mouse expressing N-terminally truncated DSG3 revealed dramatically reduced numbers of smaller and structurally altered desmosomes. Disruption of desmosomes was especially prominent in the paws and tail. A marked increase in cell proliferation was elicited in areas where cell adhesion was not completely lost (Allen et al., 1996). In HaCaT and MDCK cells, a DSG3 knockdown resulted in impaired desmosome assembly and defects in cell adhesion as well as reduced proliferation with a reduction in G1/S phase transition and reduced colony size. In contrast, overexpression of DSG3 promoted cell proliferation (Mannan et al., 2011). In agreement, DSG3 was highly expressed in head and neck cancer and its expression correlated with proliferative and invasive properties of these cancer cell lines (Chen et al., 2007). Mechanistically, DSG3 silencing induced changes in desmosome composition with a loss of PG from the cell membrane and its translocation to the nucleus. This promoted an interaction of PG with the transcription factor TCF. Since PG is a negative regulator of TCF, nuclear PG alleviated TCF’s transcriptional activity and as a consequence, expression of c-MYC and cyclin D1 leading to a cell cycle arrest at the G0/G1 phase (Chen et al., 2013). Since the knockdown DSG3 reduced the expression and activation of EGFR (Ri et al., 2019), DSG3 might also regulate proliferation through EGFR signaling. Moreover, a crosstalk between DSG3 and EGFR signaling has been suggested in several reports dealing with PV pathogenesis. However, DSG3-mediated control of Hippo signaling by sequestration of YAP may also contribute to DSG3-dependent control of keratinocyte proliferation (Uttagomol et al., 2019) suggesting that DSG3 may contribute to coordinate cell signaling pathways to control CIP.

Mice lacking DSC1 show epidermal fragility accompanied by barrier defects and abnormal differentiation as well as epidermal thickening and hyperproliferation. As in DSG3-overexpressing skin, proliferating cells were not restricted to the basal layer, but also detected in suprabasal cells suggesting a role of DSC1 in suppressing proliferation by a so far unknown mechanism (Chidgey et al., 2001). However, the ectopic expression of DSC1 in basal keratinocytes under the control of the KRT14 promoter revealed no changes in keratinocyte proliferation, stratification, or differentiation (Henkler et al., 2001).

The general knockout of DSC2 has no obvious phenotype, suggesting compensatory mechanism of other desmosomal cadherins in vivo (Rimpler, 2014). However, in enterocytes DSC2 knockdown increased proliferation as indicated by elevated numbers of cells in S phase and activation of EGFR/AKT/β-catenin signaling (Kolegraff et al., 2011). A similar observation was made in prostate cancer cells, where a DSC2 knockdown led to enhanced expression of the cell cycle regulators cyclin D1, CDK2, cyclin B1, and CDK1 and promoted proliferation whereas overexpression of DSC2 led to downregulation of the same genes (Jiang and Wu, 2020). Taken together, these results suggest a role of DSC2 in suppressing proliferation in agreement with a role as a tumor suppressor.

A DSC3 knockout revealed severe epidermal hyperplasia in adult mice due to increased basal cell proliferation and reduced cell adhesion with skin blistering and hair loss but did not affect desmosome size (Chen et al., 2008). In agreement with a proliferation suppressive function, DSC3 downregulation by promoter methylation was reported in lung cancer (Cui et al., 2012) and prostate cancer, where DSC3 depletion correlated with poor prognosis (Pan et al., 2014). Cui et al. (2012) reported that DSC3 decreases EGFR/RAS/RAF/MAPK signaling in human lung cancer cells. High expression of DSC3 resulted in reduced phosphorylation of ERK1/2 and G0/G1 cell cycle arrest which blocked proliferation, whereas knockdown of DSC3 increased the amount of phospho-ERK1/2 (Cui et al., 2012). A negative correlation between DSC3 expression, PI3K/AKT signaling and proliferation was also found in colorectal cancer (Cui et al., 2019). However, conflicting results have been reported concerning DSC3’s role in cancer where Dsc3 either suppressed or facilitated proliferation, depending on tumor or cell type. For example, DSC3 was highly expressed in ovarian cancer cells, and promoted proliferation by a regulatory loop of DSC3, EGFR and PI3K/AKT signaling through follicle stimulating hormone (Yang X. et al., 2015).

Taken together, desmosomal cadherins appear to be critical regulators of context dependent proliferation control. Available data on the molecular mechanisms suggest that many of the effects converge on EGFR/MEK/ERK and PI3K/AKT-mediated signaling (summarized in Figure 2).

The targeted deletion of PG in basal keratinocytes promoted their proliferation (Li et al., 2012). Since PG is regulated through EGFR signaling and can suppress p38MAPK activation, PG may modulate EGFR-dependent control of proliferation (Spindler et al., 2014). PG has been shown to control the transcription of proliferation-promoting genes. Although skeletal muscle lacks “classic” desmosomes, they express several desmosomal proteins. In normal muscle, PG associated with the insulin receptor and the p85 subunit of PI3K to promote PI3K-AKT-Forkhead box O1 (FOXO1) signaling required for muscle cell growth and survival (Cohen et al., 2014). Moreover, PG silencing reduced the expression of AKT and attenuated insulin signaling including insulin-induced glucose uptake in adipocytes (Negoita et al., 2020). Whether PG is involved in regulating insulin sensitivity in epithelial cells remains to be determined.

PKP2 is associated with proliferation control through EGFR signaling: PKP2 interacted with the EGFR via its N-terminal domain and enhanced EGF-dependent and EGF-independent EGFR dimerization and phosphorylation (Figure 2). In support, PKP2 knockdown reduced EGFR phosphorylation and attenuated EGFR-mediated signal activation, resulting in a significant decrease in proliferation and migration of breast cancer cells (Arimoto et al., 2014). In lung adenocarcinoma, PKP2 knockdown suppressed proliferation as indicated by reduced numbers of cells in S phase (Wu et al., 2021) whereas PKP2 overexpression led to enhanced proliferation and colony formation (Hao et al., 2019). PKP2 is mainly expressed in cardiomyocytes and heterozygous mutations in the PKP2 gene are a common cause of ACM (Gerull et al., 2004). Therefore, many studies have focused on its role in cardiomyocytes and have detected a link between PKP2 and proliferation control. PKP2 knockdown in HL-1 cardiomyocytes suppressed E2F1 transcription required for G1/S phase progression and proliferation (Gurha et al., 2016). In contrast to these reports pointing to a proliferation promoting function of PKP2, Matthes et al. (2011) reported enhanced Bromodeoxyuridine (BrdU) incorporation in response to PKP2 depletion in explants from neonatal rat hearts, indicative of a proliferation suppressive function of PKP2. So far, it is not known if these contradictory findings can be explained by distinct signaling pathway activation in the various model systems which may result in differential PTMs of PKP2. These could switch PKP2 dependent functions in a similar way as described for PKP1 as a function of IGF1 signaling.

The contribution of all three PKPs to cancer appears to be context dependent and a result of their multiple functions in cell adhesion and signaling (Hatzfeld et al., 2014). Breuninger et al. (2010) studied the role of PKPs in prostate cancer cells. PKP3 expression was enhanced whereas PKP1 and PKP2 were reduced or unaffected, respectively. Overexpressed PKP3 localized with other desmosomal proteins at cell membranes but in addition in the cytoplasm and enhanced BrdU incorporation, which suggested a pro-proliferative role of PKP3 (Breuninger et al., 2010). High PKP3 expression was also observed in non-small cell lung carcinoma, which correlated with poor prognosis and survival. PKP3 knockdown in these cancer cells led to impaired growth, whereas overexpression promoted cell growth (Furukawa et al., 2005). The molecular mechanism how PKP3 modulates proliferation is so far not understood. An attractive possibility could be that PKP3 besides being regulated itself by RSK downstream of EGFR signaling, modulates EGFR pathway activity in a feedback loop.

Evidence from diseases caused by DSP haploinsufficiency suggested that alterations in DSP expression caused disruption of tissue structure but in addition changes in keratinocyte proliferation (Najor, 2018; Lee and McGrath, 2021). During embryogenesis, DSP is required to establish polarity and assemble desmosomes. DSP knockout embryos did not survive beyond E6.5, owing to a loss or instability of desmosomes and tissue integrity. Moreover, embryos were significantly smaller than normal and proliferation was considerably reduced as judged by decreased BrdU incorporation (Gallicano et al., 1998). However, it is not clear to what extent the reduced proliferation was directly linked to DSP loss or if the gross perturbation of tissue integrity indirectly impeded proliferation. In human HaCaT keratinocytes, DSP was shown to regulate cell cycle progression and proliferation. DSP knockdown not only disturbed desmosome number as indicated by reduced levels of all major desmosomal proteins, but also increased BrdU incorporation, indicating an increase in cells in S phase. Proliferative changes were associated with elevated activation of ERK1/2 and AKT which was sustained when cells reached confluence, whereas control cells downregulated ERK activity upon confluence suggesting a role of DSP in CIP (Wan et al., 2007). In cardiac but not in epidermal cells, DSP loss elevated the activity of K-RAS, an upstream activator of ERK1/2, confirming a role of DSP in suppressing mitogenic signaling (Kam et al., 2018). Schmitt-Graeff et al. (2007) reported downregulation of DSP and PKP1 during progression to SCC. Proliferative activity was inversely correlated with desmosomal protein expression in patient samples from SCC, which is compatible with an anti-proliferative and tumor suppressive role for DSP (Schmitt-Graeff et al., 2007). Many other studies did not detect a direct role of DSP in regulating proliferation. For example, a DSP knockout in human keratinocytes led to a loss of desmosomes with impaired cellular adhesion but did not affect proliferation (Wanuske et al., 2021). In an intestine specific DSP knockout, proliferation was also not affected. Surprisingly, cellular adhesion was maintained and keratin localization was unaltered in this tissue, although the intermediate filaments were not anchored at desmosomes any more (Sumigray and Lechler, 2012). Thus, the role of DSP in proliferation requires further studies to elucidate the context that enables a growth-suppressive function of DSP via ERK signaling. Although DSP reveals a substantial extradesmosomal pool, the function of this pool remains essentially elusive. In an attempt to identify DSP interactions that might modulate canonical or non-canonical desmosome functions, a targeted proximity labeling assay was performed in epidermal keratinocytes. Quantitative mass spectrometry analysis identified a diverse array of new interactions with broad molecular functions including transcription factors and transcriptional coactivators (including YAP), translation initiation factors and many regulatory proteins (Badu-Nkansah and Lechler, 2020). Interestingly, numerous SH2/SH3 adapter proteins as well as protein tyrosine phosphatases have also been identified, further supporting the assumption of a close connection between desmosomes and growth factor signaling. Elucidating the role of such interactors will substantially advance our understanding of context dependent DSP functions.

The overall rate of protein synthesis has to keep pace with the proliferation rate to maintain cell size and functionality (Miettinen et al., 2019). Therefore, cell proliferation strongly depends on the synthesis of new proteins (Pardee, 1989; Polymenis and Aramayo, 2015). This is supported by reports showing that modifications of the translation machinery can affect cell proliferation rates and that deregulation of protein synthesis can be a driver of cell transformation (Silvera et al., 2010; Truitt and Ruggero, 2016). mRNA translation is mostly controlled at the level of initiation during which the small 40S ribosomal subunit is recruited to the 5′-cap structure of the mRNA and scans the mRNA 5′-UTR for the start codon. Following recognition, the 80S initiation complex is assembled at the start codon and elongation will proceed. Translation initiation requires several eukaryotic translation initiation factors (eIFs) and is partly regulated by the mammalian target of rapamycin (mTOR) signaling pathway which senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis (Ma and Blenis, 2009). mTOR signaling via ribosomal S6 kinases (S6Ks) regulates eIF4E binding to the mRNA cap and recruitment of eIF4A, eIF4B, and eIF4G. eIF4A is an RNA helicase that is capable of unwinding mRNA secondary structures facilitating the translation of mRNA species containing inhibitory secondary structures in their 5′ untranslated region. PKP1 was identified as a component of the cap-binding translation initiation complex where it associated directly with eIF4A1. PKP1 not only stimulated the recruitment of eIF4A1 into the cap complex but also promoted its helicase activity. The stimulation of translation upon PKP1 overexpression correlated with an upregulation of proliferation and cell size (Figure 3; Wolf and Hatzfeld, 2010; Wolf et al., 2010).

The dual function of PKP1 in increasing desmosome size and adhesion on the one hand and in stimulating translation and proliferation on the other hand pointed to a role of this protein in mediating CIP. Obviously, PKP1’s role depended on its localization which was regulated by the IGF1/AKT2 signaling axis, a pathway implicated in the general regulation of translation. Unregulated activation of AKT2 was observed in papillomas and in human papilloma virus (HPV) induced epidermal tumors and was characteristic of SCC (O’Shaughnessy et al., 2007). Moreover, AKT2 was upregulated by ultraviolet (UV) radiation, the most important skin carcinogen (Sully et al., 2013). These data place PKP1 among the effectors of AKT2 signaling and suggest a role of PKP1 in the uncontrolled proliferation of certain skin carcinoma. In agreement, Wolf et al. (2013) showed that a PKP1 mutant that mimics AKT2 induced phosphorylation confers anchorage independent growth.

Gene expression is primarily controlled at the transcriptional level. Li et al. (2012) reported epidermal thickening, impaired inflammation responses, and disrupted desmosome assembly in epidermis specific PG knockout mice. Proliferation was increased as shown by elevated BrdU incorporation, with proliferating cells restricted to the basal layer (Li et al., 2012). In MCF-7 breast cancer cells, overexpression of PG suppressed proliferation, whereas its knockdown promoted proliferation. This correlated with increased levels of tumor promoters such as ERBB2 and Snail and decreased levels of tumor suppressors. Transcriptional activity of the tumor suppressor p53 was enhanced in the presence of PG suggesting that PG regulates gene expression in conjunction with p53 (Aktary et al., 2013, 2017). PG was also reported to repress expression of the c-MYC proto oncogene in a LEF-1 dependent way suggesting that PG blocked LEF-1 transcriptional activity. Since PG-mediated suppression of MYC was similar in both wild type and β-catenin-null keratinocytes, this effect did not depend on a competition between PG and β-catenin for LEF-1. Moreover, ChIP experiments with PG antibodies demonstrated an association of PG and LEF-1 with the MYC promoter in keratinocytes undergoing growth arrest, supporting a role of PG in transcriptional regulation (Williamson et al., 2006). PG may also function to potentiate death in cells damaged by apoptotic stimuli, perhaps limiting the potential for the propagation of mutations and cellular transformation. Since PG knockout keratinocytes showed increased levels of anti-apoptotic B-cell lymphoma extra-large (BCL2L1 alias BCL-XL), the resulting protection from apoptosis might also be mediated by the regulation of transcription (Dusek et al., 2007).

In Xenopus embryos, PKP3 associated with the transcription factor erythroblast transformation specific variant 1 (ETV1) and positively modulated ETV1-dependent transcriptional activation. Since ETV1 promotes metastasis of prostate cancer, one might speculate that elevated expression of PKP3 stimulates ETV1 target gene expression to promote proliferation and metastasis in prostate carcinoma (Munoz et al., 2014).

In conclusion, desmosomal proteins regulate proliferation in an adhesion-dependent and adhesion-independent manner. Desmosomal dysfunction can promote cancer development, which is accompanied by enhanced cell cycle progression, resulting in hyperproliferation and tumor growth. Some desmosomal proteins, such as DSG2, DSG3, and PKP2, are highly expressed in many cancers and promote proliferation via EGFR signaling. This promotes cell cycle entry and progression by increasing the expression of proliferation targets, such as cyclin D1, cyclin A2, and c-MYC. In contrast, DSCs seem to suppress proliferation. The role of PKP3 and DSP in regulating proliferation requires further investigation. Contradictory results on the correlation between expression and proliferation rates may be explained by different tumor entities and cell lines with considerable differences in signaling pathway activation. It is therefore necessary to fully understand the functional relationship between signaling pathway components and their desmosomal targets and how these signals control non-desmosomal functions.