Desmosome Signaling

Downloaded from http://perspectivesinmedicine.cshlp.
org/ on December 4, 2014 - Published by Cold Spring Harbor Laboratory

Press
Desmosomes: Regulators of Cellular Signaling and Adhesion in

Epidermal Health and Disease
Jodi L. Johnson, Nicole A. Najor and Kathleen J. Green
Cold Spring Harb Perspect Med 2014; doi: 10.1101/cshperspect.a015297
Subject Collection The Skin and Its Diseases
Immunology and Skin in Health and Disease Epidermal Polarity Genes in Health and Disease
Jillian M. Richmond and John E. Harris Frederik Tellkamp, Susanne Vorhagen and Carien
M. Niessen
Desmosomes: Regulators of Cellular Signaling Induced Pluripotent Stem Cells in Dermatology:
and Adhesion in Epidermal Health and Disease Potentials, Advances, and Limitations
Jodi L. Johnson, Nicole A. Najor and Kathleen J. Ganna Bilousova and Dennis R. Roop
Green
Markers of Epidermal Stem Cell Subpopulations The Genetics of Human Skin Disease
in Adult Mammalian Skin Gina M. DeStefano and Angela M. Christiano
Kai Kretzschmar and Fiona M. Watt
Melanoma: Clinical Features and Genomic Modeling Cutaneous Squamous Carcinoma
Insights Development in the Mouse
Elena B. Hawryluk and Hensin Tsao Phillips Y. Huang and Allan Balmain
Psoriasis p53/p63/p73 in the Epidermis in Health and
Paola Di Meglio, Federica Villanova and Frank O. Disease
Nestle Vladimir A. Botchkarev and Elsa R. Flores
The Dermal Papilla: An Instructive Niche for Advanced Treatment for Basal Cell Carcinomas
Epithelial Stem and Progenitor Cells in Scott X. Atwood, Ramon J. Whitson and Anthony E.
Development and Regeneration of the Hair Follicle Oro
Bruce A. Morgan
Cell Therapy in Dermatology Diversification and Specialization of Touch
Gabriela Petrof, Alya Abdul-Wahab and John A. Receptors in Skin
McGrath David M. Owens and Ellen A. Lumpkin
Melanocytes and Their Diseases Long Noncoding RNA: Significance and Potential
Yuji Yamaguchi and Vincent J. Hearing in Skin Biology
Derrick C. Wan and Kevin C. Wang
For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/
Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved
Downloaded from http://perspectivesinmedicine.cshlp.org/ on December 4, 2014 - Published by Cold Spring Harbor Laboratory
Press
Desmosomes: Regulators of Cellular Signaling

and Adhesion in Epidermal Health and Disease
Jodi L. Johnson1,2, Nicole A. Najor1, and Kathleen J. Green1,2

1
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
2
Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
Correspondence: kgreen@northwestern.edu
Desmosomes are intercellular junctions that mediate cell– cell adhesion and anchor the
intermediate filament network to the plasma membrane, providing mechanical resilience
to tissues such as the epidermis and heart. In addition to their critical roles in adhesion,
desmosomal proteins are emerging as mediators of cell signaling important for proper cell
and tissue functions. In this review we highlight what is known about desmosomal proteins
regulating adhesion and signaling in healthy skin—in morphogenesis, differentiation and
homeostasis, wound healing, and protection against environmental damage. We also
discuss how human diseases that target desmosome molecules directly or interfere indirectly
with these mechanical and signaling functions to contribute to pathogenesis.
www.perspectivesinmedicine.org
esmosomes are intercellular junctions that er tissue-specific desmosome proteins include

D strengthen mechanically challenged tissues
by linking intermediate filaments of adjoin-
Perp ( p53 apoptosis effector related to PMP-
22) (Ihrie and Attardi 2005) and the outer epi-
ing cells. They are crucial for both embryonic dermal cornified envelope components corneo-
development and adult tissue integrity. Insults desmosin, periplakin, envoplakin, involucrin,
against or mutations in desmosomal proteins and kazrin (Groot et al. 2004; Sonnenberg and
lead to potentially lethal skin and heart diseases Liem 2007; Leclerc et al. 2009). The desmo-
(Bazzi and Christiano 2007; Amagai and Stanley somal cadherins join cells together through
2012; Petrof et al. 2012; Kowalczyk and Green their extracellular domains and associate with
2013). Pg and the Pkps through their intracellular do-
Members of three protein families make up mains. The cadherin – armadillo complex binds
the core components of the desmosome (Figs. 1 in turn to Dp, which tethers the intermedi-
and 2): cadherins including desmogleins and ate filament network to the junctional plaque
desmocollins (Dsgs, Dscs), armadillo proteins (Green and Simpson 2007; Kowalczyk and
including plakoglobin and plakophilins (Pg and Green 2013). The ability to confer mechanical
Pkps), and a plakin, desmoplakin (Dp) (Green strength through interaction with flexible,
and Simpson 2007; Delva et al. 2009). Oth- mechanically resilient intermediate filaments
Editors: Anthony E. Oro and Fiona M. Watt

Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org
Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015297
Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297
1
Press
J.L. Johnson et al.
Dense midline
Plasma membrane
Outer dense
Dsc
Dsg
plaque
Pg
Pkp
Dp
Inner dense
plaque
IF
Figure 1. Desmosome structure and organization. Electron micrograph of a desmosome from bovine tongue
epithelium overlaid with a representation of the membrane and plaque components. Desmosomes are com-
posed of cadherins (Desmoglein, Dsg; Desmocollin, Dsc), armadillo proteins (Plakoglobin, Pg; Plakophilin,
Pkp), and a plakin (Desmoplakin, Dp), which act as a cytolinker to tether the desmosome to the intermediate
filaments (IF).
distinguishes desmosomes from a similar cad- during stratification. Different desmosomal cad-
herin-based organelle, the adherens junction, herins have inherent differences in adhesive
which interacts with the more rigid actin cyto- strength (Hartlieb etal. 2013). Therefore, switch-
skeleton (Chu et al. 2004; Mucke et al. 2004; ing components in each layer may allow cell
Gardel et al. 2008). plasticity in the lower, proliferative layers and
Desmosomal components change as kerati- increased strength and barrier function in the
nocytes differentiate and stratify (Fig. 2). For upper layers. In addition to their adhesive func-
instance, Dsg2 is concentrated in the basal pro- tions, desmosomal components regulate intra-
liferating layers, whereas Dsg1 is first expressed cellular signaling (Green and Gaudry 2000;
as cells transit out of the basal layer and becomes Green and Simpson 2007; Kowalczyk and Green
progressively concentrated in suprabasal layers 2013), and forced expression of a cadherin in
2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Press
Desmosomes in Epidermal Health and Disease
Plakin Armadillo Cadherin
granulosum corneum
Stratum
family family family
Dsg4
Pkp1
Dsc1
Dsg1
Dp
Pkp3
Pg
Stratum
spinosum
Stratum
Stratum
basale
Dsg3
Dsg2
Pkp2
Dsc2
Dsc3
Dsg4
KLF-4 ZEB MAL/ SLUG* CDX-1* C/EBP-α C/EBP-β p63
SMAD1
KLF-5 MRTF* Brn-3b* CDX-2* C/EBP-γ C/EBP-δ GRHL1
SMAD4
p63 SRF* TCF-4 p63 KLF-4
SMAD5
LEF-1 p53 KLF-5
LEF-1
PG TCF-4
FOXN-1
cREL/ LEF-1
NICD
NF-κB PG
HoxC12
HoxC13
Figure 2. Desmosome differential protein expression pattern in epidermis and the transcription factors linked to
their regulation. Several of the desmosomal components display a unique spatial pattern of expression within the
epidermis (depicted as triangles and rectangles). We have summarized the transcriptional regulation of the
desmosomal components from multiple cell types in Table 1. Desmosomal regulators that have been verified in
the epidermis (no asterisk) are distinguished from those verified in other tissues (asterisk). Transcription factors
regulating Pkp1, Dsg3, and Dsg2 are putative or unknown.
the “wrong” layer can lead to alterations in pro- TRANSCRIPTIONAL REGULATION

liferation/survival and differentiation (Henkler OF DESMOSOMAL COMPONENTS
et al. 2001; Hanakawa et al. 2002; Merritt et al.
2002; Hardman et al. 2005; Brennan et al. 2007, The mechanisms responsible for establishing
2010). The naturally diverse expression of des- the spatial patterning of desmosomal compo-
mosomal components in each epidermal layer nents in stratified epithelia are not yet well un-
allows desmosomes to serve not only as nuts derstood. Desmosomal cadherin genes group
and bolts to hold cells together but also as a together on chromosome 18, whereas Pkp1-3,
tool kit to modulate form and function of the Pg, and Dp genes map to chromosomes 1, 12,
highly specialized tissue. 11, 17, and 6, respectively (Arnemann et al.
In the sections that follow, we review tran- 1991; Wang et al. 1994; Simrak et al. 1995; Cow-
scriptional programs that dictate where and ley et al. 1997a,b; Bonne et al. 1998; Whittock
when desmosomal cadherins are expressed and Bower 2003). The chromosomal grouping
and the functional implications of the result- of the desmosomal cadherins may allow for se-
ing expression patterns in health and disease. quential expression in which, for example, Dsc1
We conclude by introducing how desmosom- follows Dsg1 expression in epidermal differen-
al protein expression might be manipulated tiation, although a mechanism has not yet been
pharmacologically, taking advantage of natural elucidated (Getsios et al. 2009).
turnover processes that control junction ho- Signaling pathways involved in epidermal
meostasis. differentiation regulate keratin and desmosom-
Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 3

Press
J.L. Johnson et al.
al protein expression in keratinocytes, such as factors to desmosomal component promoters

Notch, transforming growth factor b (TGF-b), has only been shown in a few instances (Table
IkB kinase (IKK), Ras/mitogen activated pro- 1) (Bazzi et al. 2009; Bailey et al. 2012; Tokon-
tein kinase (MAPK), phosphoinositide-3-kinase zaba et al. 2013). Pg itself complexes with TCF/
(PI3K), Wnt, protein kinase C or A (PKC, PKA), Lef-1 to regulate the balance of Dsc2 and Dsc3
and Rho GTPases (Dong and Chen 2009; Leitner expression (Tokonzaba et al. 2013).
et al. 2011; Lopez-Pajares et al. 2013). However, Desmosomal cadherin distribution within
links between these signaling pathways and the the stratified epidermis may in part be regulat-
specific downstream transcription factors that ed by the differential activity of transcription
regulate desmosomal protein expression have factor isoforms. For instance, the more basally
only been elucidated in a few instances. It has concentrated Dsc3 is activated by the b form
long been known that PKC signaling regulates of CCAAT/enhancer-binding protein, whereas
expression of desmosomal cadherins in kerati- Dsc1 is activated by the a isoform. This isoform
nocytes (Denning et al. 1998). Suppression of specificity suggests one potential mechanism for
PKC-a or PKC-d isoforms increases Dsg3 ex- switching between basal and suprabasal desmo-
pression, whereas suppression of PKC-d and somal cadherins during differentiation. Expres-
PKC-1 isoforms either decreases or increases sion of desmosomal components and keratins
Dsg1 levels, respectively (Szegedi et al. 2009). can be regulated by the same transcription fac-
However, the specific transcription factors which tors. For example, Ap2, HoxC13, Lef-1 and
act downstream of PKC isoforms to induce or Foxn1, which up-regulate or repress keratin ex-
inhibit desmosomal protein expression have not pression, have also been implicated as putative
yet been directly shown, even though Dsg1, or shown regulators of Dsgs, Dscs, armadillo
Dsg3, Dsc2, and Pg promoters all have putative proteins, and the associated desmosomal com-
binding sites for PKC-regulated transcription ponents periplakin and envoplakin (Byrne et al.
factors (Table 1). Recently, the Ephrin family of 1994; Silos et al. 1996; Marsden et al. 1997;
receptors and ligands has emerged as regulat- Adams et al. 1998; Aho et al. 1999; Maatta et al.
ing expression of differentiation-associated pro- 2000; Potter et al. 2001; Bazzi et al. 2009).
teins, including Dsg1 (Lin et al. 2010; Walsh Understanding how transcriptional programs
and Blumenberg 2011) but, similarly to PKC, coordinate the expression of cytoarchitectural
the specific transcription factors controlled by building blocks during differentiation will help
this pathway have not yet been determined. us better understand epidermal development,
More direct links between desmosomal hair follicle cycling, wound healing, and re-
component expression and transcriptional reg- sponses to environmental exposure.
ulators downstream of Notch, Rho, and Wnt Desmosomal components can be transcrip-
pathways have recently been shown. Notch and tionally repressed by factors such as Slug and
the transcription factor p63 regulate each other Zeb, which promote epithelial-to-mesenchymal
(Roemer 2012) and p63 has been shown by chro- (EMT) transition and wound re-epithelializa-
matin immunoprecipitation (ChIP) to bind and tion (Savagner et al. 2005; Vandewalle et al.
activate Dsg1, Dsc3, and Dp promoters (Ferone 2005; Aigner et al. 2007). Epigenetic mecha-
et al. 2013; Johnson et al. 2014). Rho-mediated nisms, including promoter methylation and his-
changes in the actin cytoskeleton lead to changes tone deacetylation (HDAC), also repress the ex-
in Srf-dependent transcription (Miralles et al. pression of desmosomal proteins, which may
2003) and Srf controls the expression of Pkp2 contribute to carcinogenesis (Potter et al. 2001;
and Dsg1, which in turn drives a program of Cui et al. 2011; Kaz et al. 2012; Yang et al. 2012).
terminal differentiation (Leitner et al. 2011; Du- The consequent loss of desmosome-mediated
bash et al. 2013), The Wnt-regulated TCF/Lef adhesion can be restored in part by HDAC in-
transcription complex has been implicated in hibitors (Shim et al. 2004; Simpson et al. 2010).
regulation of Dsg4, Dsc2, Dsc3, and Pg expres- Furthering our understanding of the transcrip-
sion but direct binding of these transcription tional programs that regulate desmosomal pro-

Press
Table 1. Transcriptional regulators of desmosomal components, representative upstream signaling pathways

regulating those transcription factors, and biological processes impacted
Biological process reported
Transcription Upstream or potentially implicated
Component factor regulator from other references Method References
Dsg1 AP-1 PKC, MAPK Proliferation, differentiation Putative Adams et al. 1998
Dsg1 AP-2 Notch Differentiation, Putative Adams et al. 1998
development,
tumorigenesis
Dsg1 0ct-2 MAPK Differentiation, Putative Adams et al. 1998
development
Dsg1 0ct-4 Wnt Development, Putative Adams et al. 1998
differentiation, maintains
stem cells, tumorigenesis
Dsg1 SP1 PKC, PKA, Differentiation, Putative Adams et al. 1998
MAPK, development
PI3K
Dsg1 NF-kB IKK Apoptosis, hair follicle Putative Adams et al. 1998
development
Dsg1 C/EBP PKA, Wound healing, Putative Adams et al. 1998
MAPK, differentiation,
PI3K tumorigenesis
Dsg1 E2A Cell commitment, growth, Putative Adams et al. 1998
differentiation in
lymphocytes, muscle cells

and neurons, EMT
Dsg1 p63 Notch Differentiation, ChIP Ferone et al. 2013;
stratification, Johnson et al.
tumorigenesis 2014
Dsg1 Grainy head-like Differentiation, cell ChIP/Rep Wilanowski et al.
1 adhesion, hair 2008
development, eyelid
development, wound
repair
Dsg1 Klf-4 NF-kB, Rho Eyelid development Rep/EMSA Swamynathan et al.
2011;
Kenchegowda
et al. 2012
Dsg1 Klf-5 NF-kB, Rho Eyelid development Rep/EMSA Kenchegowda et al.
2012
Dsg3 AP-1 PKC, MAPK Proliferation, differentiation Putative Adams et al. 1998
Dsg3 AP-2 Notch Differentiation, Putative Adams et al. 1998
development,
tumorigenesis
Dsg3 C/EBP PKA, Wound healing, Putative Adams et al. 1998
PI3K tumorigenesis
Dsg3 0ct-B2 Differentiation, Putative Adams et al. 1998
development
Dsg3 Sp1 PKC, PKA, Differentiation, Putative Silos et al. 1996
MAPK, development
PI3K
Continued

Press
J.L. Johnson et al.
Table 1. Continued
Dsg3 Glucocorticoid Differentiation, Putative Silos et al. 1996
RE stratification, skin barrier
formation
Dsg4 SMAD1 Hair follicle development ChIP/Rep Owens et al. 2008
and integrity
and integrity
and integrity
Dsg4 HoxC13 Repression of gene Rep/EMSA Bazzi et al. 2009
expression in hair follicle
Dsg4 Lef-1 Wnt Repression of gene Rep/EMSA Bazzi et al. 2009
Dsg4 FoxN1 Repression of gene Rep/EMSA Bazzi et al. 2009
Dsg4 HoxC12 Activation of gene expression Rep/EMSA Bazzi et al. 2009
in hair follicle
Dsg4 Notch (NICD) Activation of gene expression Rep/EMSA Bazzi et al. 2009
in hair follicle,
differentiation,
tumorigenesis
Dsc1 C/EBP-a PKA, Wound healing, Rep/EMSA Smith et al. 2004
PI3K tumorigenesis
Dsc1 C/EBP-d PKA, Wound healing, Rep/EMSA Smith et al. 2004
PI3K tumorigenesis
Dsc2 SP1 PKC, PKA, Differentiation, Putative Marsden et al. 1997
MAPK, development
PI3K
Dsc2 AP-1 PKC, MAPK Differentiation, Putative Marsden et al. 1997
development
Dsc2 AP-2 Notch Differentiation, Putative Marsden et al. 1997
development,
tumorigenesis
Dsc2 Pit-1 Differentiation, Putative Marsden et al. 1997
development
Dsc2 NF-kB IKK Apoptosis, hair follicle Putative Marsden et al. 1997
development
Dsc2 Retanoic acid Putative Marsden et al. 1997
RE
Dsc2 TCF-3/TCF-4/ Wnt Epidermal development— ChIP/Rep Tokonzaba et al.
Lef-1 induction of Dsc2 2013
Dsc2 Pg/Lef-1 Wnt Lef-1 presence or absence is ChIP/Rep Tokonzaba et al.
switch for Pg-regulated 2013
transcriptional activation
of Dsc3 or Dsc2
Continued

Press
Table 1. Continued
Dsc2 c-Rel/NF-kB IKK Hair follicle development ChIP/Rep Tokonzaba et al.
and integrity 2013
Dsc2 Cdx-1 Colon development, Rep/EMSA Funakoshi et al.
tumorigenesis 2008
Dsc2 Cdx-2 Colon development, ChIP/Rep Funakoshi et al.
tumorigenesis 2008
Dsc3 C/EBP-b PKA, Wound healing, Rep/EMSA Smith et al. 2004
PI3K tumorigenesis
Dsc3 C/EBP-d PKA, Wound healing, Rep/EMSA Smith et al. 2004
PI3K tumorigenesis
Dsc3 p63 Notch Differentiation, ChIP/Rep Ferone et al. 2013
stratification,
tumorigenesis
Dsc3 p53 DNA damage response, cell- ChIP Oshiro et al. 2003
cycle arrest, apoptosis,
differentiation, cell
adhesion
Dsc3 TCF-3/TCF-4/ Wnt Epidermal development— ChIP/Rep Tokonzaba et al.
Lef-1 repression of Dsc3 2013

Dsc3 Pg Lef-1 presence or absence is ChIP/Rep Tokonzaba et al.
switch for Pg-regulated 2013
transcriptional activation
of Dsc3 or Dsc2
Dsc3 Methylation Colorectal cancer Cui et al. 2011
Pg NFY and/or C/ PKA, Wound healing, Putative Potter et al. 2001
EBP MAPK, differentiation,
PI3K tumorigenesis
Pg SP-1 PKC, PKA, Differentiation, Putative Potter et al. 2001
MAPK, development
PI3K
Pg AP-2 Notch Differentiation, Putative Potter et al. 2001
development,
tumorigenesis
Pg Pea3 Wnt Development, tumorigenesis Putative Potter et al. 2001
Pg MyoD Wnt Skeletal muscle Putative Potter et al. 2001
differentiation
Pg Nkx2.5 Heart/suprabasal epidermal Putative Potter et al. 2001
layers, increased in
psoriasis/SCC, decreased
in atopic dermatitis/BCC
Pg E2 Cell commitment, growth, Putative Bailey et al. 2012
differentiation in
lymphocytes, muscle cells
and neurons, EMT
Pg Slug TGF-b, Wnt Breast cancer ChIP/Rep Bailey et al. 2012
Continued

Press
J.L. Johnson et al.
Table 1. Continued
Pg Brn-3b Breast cancer, development Rep/EMSA Samady et al. 2006
and differentiation
Pg Methylation Thyroid carcinoma cell lines Potter et al. 2001
tested
Pkp1 Methylation Progression of esophageal Kaz et al. 2012
carcinogenesis
Pkp2 Mal/Mrtf Rho Migration ChIP Leitner et al. 2011
Pkp2 Srf Rho, MAPK Migration, proliferation ChIP Leitner et al. 2011
Pkp3 Zeb MAPK, Colon cancer progression, ChIP/Rep Aigner et al. 2007
TGF-b EMT, development
Dp Klf-4 NF-kB, Rho Eyelid development Rep/EMSA Swamynathan et al.
2011;
Kenchegowda
et al. 2012
Dp Klf-5 NF-kB, Rho Eyelid development Rep/EMSA Kenchegowda et al.
2012
Dp p63 Notch Differentiation, ChIP/Rep Ferone et al. 2013
stratification,
tumorigenesis
Dp Methylation Progression of lung cancer Yang et al. 2012

The method by which the transcription factor was determined to interact with the desmosomal component promoter is
listed as either putative (the cloned promoter contained a binding site for the transcription factor, but direct association
between them has not been shown), confirmed by electrophoretic mobility shift assay (EMSA) or reporter assay (such as
luciferase, referred to as Rep), or confirmed by chromatin immunoprecipitation (ChIP). Dsg2 was excluded from the table as
there is currently no published information for its transcriptional regulation.
AP-1/2, activator protein 1/2; Oct, octamer binding; SP1, specificity protein 1; NF-kB, nuclear factor k-light-chain-
enhancer of activated B cells; TCF/Lef, high mobility group transcription factors; C/EBP, CCAAT-enhancer-binding
protein; E2A, E box binding protein, Klf, Krüppel-like factor; RE, responsive element; SMAD, bone morphogenetic protein
(BMP) pathway; Hox, homeobox transcription factor; Fox, forkhead box; Pit, pituitary-specific positive transcription factor;
Cdx, homeobox transcription factor; NFY, CCAAT binding nuclear factor; pea, Ets family member; MyoD, myogenic
regulatory factor; Nkx, homeodomain transcription factor; Brn, Pit-Oct-Unc family member isolated from brain; Mal/
MRTF, myocardin related transcription factor; SRF, serum response factor; Zeb, zinc finger E-box-binding homeobox.
tein expression will be an important prerequisite between proliferation and differentiation dur-
for pharmacologically intervening in disorders ing embryogenesis and in the adult (Allen et
involving these molecules. al. 1996; Chidgey et al. 2001; Elias et al. 2001;
Merritt et al. 2002; Kljuic et al. 2003; Hardman
et al. 2005). Forced expression of basally concen-
ROLES FOR DESMOSOME MOLECULES
trated Dsg3 in the suprabasal layers of mouse
IN MORPHOGENESIS AND HOMEOSTASIS
epidermis increases the Dsg3:Dsg1 ratio and dis-
OF STRATIFIED TISSUES
tribution to resemble that of oral epithelium
Desmosomal protein expression patterning (Elias et al. 2001). These mice show alterations
contributes not just to tissue integrity, but also in the stratum corneum and die shortly after
to signaling that controls morphogenesis and birth because of excessive transepidermal water
homeostasis. Interfering with desmosomal cad- loss. Dsg2, the most broadly expressed Dsg, is
herin expression patterns can upset the balance required for embryonic stem cell proliferation

Press
(Eshkind et al. 2002). Further, its misexpression inhibits proliferation depending on cell type,
in upper epidermal layers results in hyperplasia the latter through suppression of Erk and Akt
by engaging growth factor signaling cascades (Wan et al. 2007). In turn, growth factor signal-
that promote proliferation and survival including can convert desmosomal components from
ing PI3K/AKT, MEK-MAPK, STAT3, and NF- adhesive to pro-proliferative functions as in the
kB (Brennan et al. 2007; Brennan and Mahoney case of insulin signaling via Akt2 causing Pkp1
2009). In contrast, Dsg3 knockdown reduces cell to promote proliferation and migration (Wolf
proliferation in vitro (Mannan et al. 2011) and et al. 2013). Collectively, these observations
Dsg3 knockout mice do not show enhanced epi- suggest that the core building blocks of desmo-
dermal carcinogenesis compared with controls somes are tailored to support specific functions
(Baron et al. 2012). Dsg1, which first emerges within complex tissues and are important for
as cells stratify, is important for promoting dif- controlling epidermal homeostasis.
ferentiation through suppression of epidermal
growth factor receptor (EGFR) and Erk-1/2 sig-
DESMOSOMES AND THE EPIDERMAL
naling (Getsios et al. 2009). The adhesive ecto-
BARRIER
domain of Dsg1 is dispensable for this function,
which instead requires interaction with a newly To help maintain the skin’s barrier against
identified binding partner Erbin (ERBB2IP) the environment, desmosomes become modi-
(Harmon et al. 2013). Erbin blocks Erk signaling fied into structures called corneodesmosomes
by disrupting Ras – Raf complexes mediated by in the outermost epidermal layers. Differen-
a scaffolding protein called SHOC2. Misexpres- tiation-specific components are incorporated
sion or interferencewith other desmosomal cad- into corneodesmosomes including Dsg1, Dsc1,
herins has similarly been reported to affect epi- envoplakin, periplakin, and corneodesmosin
dermal or hair follicle differentiation (Chidgey (CDSN). CDSN is thought to support supra-
et al. 2001; Kljuic et al. 2003). These data support basal adhesion through a glycine-rich domain
the idea that basal and suprabasal desmosomal within its amino terminus. The cornified enve-
cadherins play a “yin – yang” role to control the lope forms along the plasma membrane between
proper balance of proliferation and differentia- desmosomes through transglutaminase-medi-
tion in tissue. ated cross-linking of involucrin to itself and to
Desmosome molecules may control tissue Dp, periplakin, and envoplakin (Ruhrberg et al.
homeostasis in part through armadillo protein- 1997; Steinert and Marekov 1999). A differenti-
dependent signaling. Dscs1-3, Pg, Pkp2, and Dp ation-specific periplakin binding protein called
suppress b-catenin, which is pro-proliferative, kazrin assists in promoting differentiation and
through altering b-catenin subcellular localiza- formation of the cornified envelope, acting to
tion, competing for b-catenin DNA binding scaffold multiple cytoskeletal elements (Groot
sites to alter its transcriptional function, and et al. 2004) and to regulate cell shape through
regulating b-catenin expression and stability Rho GTPases (Sevilla et al. 2008; Nachat et al.
(Chen et al. 2002; Hardman et al. 2005; Thoma- 2009). Thus, just as the early stages of epidermal
son et al. 2010; Kolegraff et al. 2011; Aktary and differentiation require proper expression and
Pasdar 2012; Yang et al. 2012). Pg has also been distribution of desmosomal cadherins, so do
shown to reduce the proliferative capacity in later differentiation states require specialized
both normal epidermis and cancer cells, and desmosome functions to ensure proper barrier
can act directly on transcriptional targets or information.
directly by competing for b-catenin binding fac- Desmosomes are subject to regulation by
tors (Parker et al. 1998; Charpentier et al. 2000; environmental interactions, yet at the same time
Aktary and Pasdar 2012). participate in epidermal responses to stressors
Cadherin-associated proteins also regulate like humidity and heat. Dry conditions increase
growth factor effector signaling. For instance, the number of corneodesmosomes and Dsg1
Dp either supports (Gallicano et al. 1998) or content, associated with decreased desquama-

Press
J.L. Johnson et al.
tion and scaly skin in mice (Rawlings et al. 1995; by UVB (290- to 320-nm wavelengths) exposure
Sato et al. 1998). Desmosomes may protect in keratinocytes beginning to differentiate. Im-
against temperature extremes, as survival of portantly, ectopic Dsg1 expression counteracts
MDCK cells with tight junctions and desmo- UVB-induced loss of differentiation markers
somes is nearly one log higher than cells lacking (Johnson et al. 2014) indicating that desmoso-
tight junctions and desmosomes after exposure mal components contribute directly to epider-
to 45˚C (Ning and Hahn 1994). Whether this mal responses to carcinogenic exposure.
protective effect applies to the epidermis is not Desmosome molecules are also involved
known and no mechanism explaining how des- in apoptosis associated with UV exposure and
mosomes protect cells against temperature ex- other environmental stresses (Dusek et al. 2006,
tremes has yet been elucidated. However, it is 2007; Nava et al. 2007; Baron et al. 2012). Where-
interesting to note that heat, which induces as loss of Dsg1 protects keratinocytes against
heat shock protein 70 (HSP70) chaperones in UVC-mediated apoptosis, Dsg3 knockout mice
the epidermis (Matsuda et al. 2013), also drives show no changes in apoptosis following chronic
desmosomal Pkps to stress granules where they UVB exposure (Dusek et al. 2006; Baron et al.
interact with RNA binding proteins (Hofmann 2012). Pg has been reported to be both pro- and
et al. 2006). It is tempting to speculate that this antiapoptotic (Aktary and Pasdar 2012). For in-
movement of Pkps may help regulate increased stance, loss of the GTPase Rnd3 protects kerati-
expression or recruitment of HSPs or otherwise nocytes from cisplatin-induced apoptosis; sen-
protect cells against heat-induced death. When sitivity to cisplatin is restored when Pg, but not
HSP40 is depleted in cultured human keratino- Dp, is knocked down in a Rnd3-deficient back-
cytes, expression levels of keratins 5, 14, and 10 ground (Ryan et al. 2012). The mechanisms
increase and keratin ubiquitination decreases linking Pg to cell survival are not clear, although
(Yamazaki et al. 2012) suggesting that heat may the authors speculate it may be through regula-
repress intermediate filaments, which would tion of cell survival effectors such as Bcl-2. An-
impact the epidermal structure. HSP Apg-2 other study indicates that keratinocytes derived
binds to ZO-1, a tight junction protein that is from Pg null mice are protected from apoptosis,
important for epidermal barrier formation. The with null cells showing delayed mitochondrial
Apg-2-ZO-1 interaction seems to promote as- cytochrome c release and activation of caspase-3
sembly of tight junctions as depletion of Apg-2 as well as increased Bcl-xL expression (Dusek
slows their new formation (Aijaz et al. 2007). et al. 2007). The role of desmosome molecules
Therefore, mechanisms behind how heat may in cell survival or death may thus be stimulus
impact epidermal morphogenesis and barrier and/or context dependent. Together these re-
function are beginning to unfold. sults suggest that whereas desmosomes are fre-
Desmosomes are affected by exposure to quently targeted by environmental factors, des-
carcinogens including tobacco smoke, air pollu- mosome molecules also aid epidermal recovery
tion, and UV light (White and Gohari 1984; following stress.
Tachikawa et al. 1986). UV-induced sunburn
cells (defined by pyknotic nuclei and eosino-
ALTERATIONS IN DESMOSOMAL
philic cytoplasm) stain negatively for Dsgs and
COMPONENTS AND CELL SIGNALING
Dps (Bayerl et al. 1995) and reduced desmosome
IN EPITHELIAL CANCERS
molecule transcripts are frequently observed in
UV-exposed keratinocytes (Li et al. 2001; Mu- The loss of desmosomes has been associated
rakami et al. 2001; Sesto et al. 2002; Rundhaug with advanced epithelial tumor grade, increased
et al. 2005). UVC (below 290 nm wavelength) metastasis and poor prognosis (Dusek and At-
results in caspase-dependent cleavage of Dsg1 tardi 2011; Aktary and Pasdar 2012). However,
and redistribution of Dsg1 from cell borders down-regulation of desmosomes is frequently
into the cytoplasm (Dusek et al. 2006). In line an earlier event in carcinogenesis than down-
with these findings, Dsg1 and Dsc1 are reduced regulation of adherens junctions (Dusek and

Press
Attardi 2011) suggesting that desmosomal com- victronectin-dependent or fibronectin-depen-

ponents suppress both early and late stages of dent src signaling (Todorovic et al. 2010; Franzen
carcinogenesis. Expression of desmosomal cad- et al. 2012) and Dp by inhibiting the Wnt/b-
herins in the proper epidermal layer is an impor- catenin signaling pathway (Yang et al. 2012).
tant factor in suppressing carcinogenesis. Sup- Finally, Perp, a p53/p63 regulated pro-
porting this idea, misexpression of Dsg2 in the tein that promotes desmosome assembly and
upper epithelial layers in transgenic mice leads strength, promotes UVB-induced apoptosis and
to an increase in precancerous papillomas and suppresses UV-induced tumorigenesis in mice
susceptibility to chemically induced carcino- (Beaudry et al. 2010). Because Perp and Dsc3
genesis (Brennan et al. 2007; Brennan and Ma- are transcriptionally regulated by p53 (Oshiro
honey 2009). Multiple signaling pathways are et al. 2003; Reczeket al. 2003), p53 mutation dur-
increased by misexpression of Dsg2 including ing carcinogenesis could lead to defective des-
EGFR and NF-kB, PI3K/AKT, MEK/MAPK, mosomes, reduced intercellular adhesion, and
and STAT3, suggesting that regulation of signal- altered desmosome component-mediated cell
ing by desmosomal components is important signaling. Collectively, these data suggest that
for prevention of tumorigenesis. Whereas mis- desmosomes suppress cancer-promoting sig-
expression of normally basal Dsg2 promotes naling pathways that drive proliferation and
EGFR and other growth-related pathways, loss metastasis in multiple epithelia.
of suprabasal Dsg1 results in a failure to down-
regulate EGFR/MAPK signaling required for
DESMOSOMES IN EPIDERMAL
normal differentiation. Through its association
AUTOIMMUNE DISORDERS AND UNDER
with the scaffolding protein Erbin, Dsg1-depen-
ATTACK BY TOXINS
dent inhibition of Ras-Raf signaling could be
important for cancer prevention because aber- The autoimmune skin disorders pemphigus
rant Ras signaling is oncogenic. In line with this, and paraneoplastic pemphigus are associated
Dsg1’s loss during head and neck cancer pro- with the presence of circulating autoantibodies
gression has been reported as a better indicator attacking desmosomal components including
of poor prognosis than loss of E-cadherin Dsg1, Dsg3, Dsc3, and possibly Pkp3, bullous
(Wong et al. 2008). In addition, some basal cell pemphigoid antigen 1, envoplakin, periplakin,
carcinomas (BCCs) show reduced Dsg1 cell sur- and Perp (Koulu et al. 1984; Amagai et al. 1991;
face expression and cytoplasmic Erbin localiza- Nguyen et al. 2009; Mao et al. 2010; Yong and
tion (Tada et al. 2000; Lebeau et al. 2005). Re- Tey 2012; Kalantari-Dehaghi et al. 2013) and
duced Dsg3 and up-regulated Dsg2 have also reviewed recently by several groups (Amagai
been reported in human head and neck squa- and Stanley 2012; Grando 2012; Cirillo and
mous cell carcinoma (Teh et al. 2011). Loss of Al-Jandan 2013). Although a potential role for
Dsg2 later in cancer progression, for instance antibodies directed against cytoplasmic com-
through endocytic turnover which has been ponents in disease pathogenesis has been sug-
shown to occur in response to EGFR signaling, gested, the majority of data point to Dsg3 and
may promote loss of adhesion and invasion/ Dsg1 as the primary targets in pemphigus vul-
metastasis (Klessner et al. 2009). garis and foliaceus (see Fig. 4). Steric hindrance
Desmosomal plaque components Dp, Pg, caused by antibody binding has been suggested to
and Pkps are also emerging as critical tumor interfere with desmosomal cadherin ectodomain
and migration suppressors in a variety of cell interaction to cause skin blistering in pemphi-
types including prostate (Franzen et al. 2012), gus; however, autoantibody binding also pro-
lung (Yang et al. 2012), colon (Khapare et al. motes Dsg internalization and activates signal-
2012), pancreas (Chun and Hanahan 2010), ing pathways, most notably p38/MAPK. Dsg3
and skin (Yin et al. 2005). Pg and Dp have both loss and/or autoantibody-dependent increases
been implicated in regulating cell signaling to in p38/MAPK signaling decrease the activity
suppress cell migration—Pg through regulating of the small GTPase RhoA, thus destabilizing

Press
J.L. Johnson et al.
the actin cytoskeleton (Spindler and Waschke keratodermas, hypotrichosis, wooly hair, ar-
2011). Accordingly, direct RhoA inhibition leads rhythmogenic cardiomyopathy (ARVC), and
to pemphigus skin blistering (Waschke et al. dilated cardiomyopathy (Kowalczyk and Green
2006). In addition to its negative effects on des- 2013). Several of these diseases are lethal in
mosome function, Dsg3 internalization also humans and embryos from a number of ani-
promotes loss of E-cadherin through Src, possi- mal models of desmosome diseases die before
bly thereby having a more general effect on cell – birth or shortly thereafter because of skin and
cell adhesion (Tsang et al. 2010, 2012b). Howev- heart defects (Thomason et al. 2010; Kowalczyk
er, others report that siRNA-mediated silencing and Green 2013). Only Pkp3 and Dsc1 have so
of Dsg1 and/or Dsg3 does not significantly affect far not been associated with mutations leading
the observed IgG-dependent increase in Src and to human disease. However, Dsc1 and Dsg1 in
EGFR signaling, suggesting that other targets corneodesmosomes are targeted for degrada-
may be involved in activating these tyrosine ki- tion by hyperactive proteases and kallikrein pep-
nases (Grando 2012). tidases when the protease inhibitor LEKT1
Dsg1 is a target for Staphylococcus ex- (lympho-epithelial Kazal-type related inhibi-
foliative toxin in staphylococcal scalded skin tor) is mutated in Netherton syndrome. Skin
syndrome (SSSS) (Amagai and Stanley 2012; allergy, inflammation, scaling, and hypotricho-
Kowalczyk and Green 2013). Pg and Dsg2 ex- sis are the result (Descargues et al. 2006; Hovna-
pression reduces the blistering associated with nian 2013).
attack by these toxins (Brennan et al. 2010; Phenotypes resulting from mutations in
Simpson et al. 2010). Use of therapeutic agents desmosomal proteins may arise not only from
that increase expression of desmosomal cadher- defective adhesion, but also from alterations in
ins and Pg such as EGFR inhibitors, histone de- cell signaling cascades. In normal skin, the cyto-
acetylase inhibitors, or tyrosine phosphatase in- plasmic tail of Dsg1 binds Erbin-Shoc2 com-
hibitors like sodium pervanadate (Lorch et al. plexes to keep Shoc2 away from Ras (Fig. 3).
2004; Garrod et al. 2008; Simpson et al. 2010; However, in tissue biopsies taken from SPPK
Aktary and Pasdar 2012) may lessen the severity patients with Dsg1 haploinsufficiency, increased
of blistering in pemphigus and Staphylococcal Ras-SHOC2 and decreased Erbin-SHOC2 co-
infections. localization occurs, offering a possible explana-
The cellular responses to pemphigus anti- tion for the observed impairment of differ-
bodies and Dsg-specific toxins have facilitated entiation and epidermal hyperplasia (Fig. 4)
a better understanding of fundamental signal- (Harmon et al. 2013). Dsg1-mediated regula-
ing/assembly circuits that are likely to make tion of Erk/MAPK signaling may also play a
important contributions to cell homeostasis. role in ectodermal dysplasias because a tran-
However, much is yet to be done to determine scriptional regulator of Dsg1, p63, is frequently
the relative contribution of signaling-dependent mutated or misregulated in ectodermal dyspla-
and -independent mechanisms to disease path- sias (Ferone et al. 2013).
ogenesis in vivo (Mao et al. 2011, 2013; Saito Mutations in Dsg2, Dsc2, Pkp2, Pg, and Dp
et al. 2012). have all been implicated in ARVC, which pre-
sents with or without accompanying cutaneous
symptoms (Fig. 4). It is not yet clear whether
ROLE OF DESMOSOMES IN
ARVC results from the response to mechanical
PATHOGENESIS OF INHERITED SKIN
stress imposed on weakened cell – cell junctions,
AND HEART DISEASE
or whether more direct desmosome-dependent
Mutation of desmosomal components in hu- signaling contributes to cardiac myocyte apo-
mans leads to skin and heart diseases including ptosis, fibrofatty deposition, and lethal arrhyth-
skin fragility-ectodermal dysplasia syndrome, mias. The existing data would support the idea
lethal congenital epidermolysis bullosa, striate that both can occur. Pg loss is a diagnostic fea-
palmoplantar keratoderma (SPPK) and other ture of ARVC (Asimaki et al. 2009) and its trans-

Press
EGF
Cytoplasm
Dsg1
Dsc
Ras GDP
P P Dynamic
GTP remodeling/
P P
decrease in
P P Grb2 Sos hyperadhesion SERCA2
Erbin
EGFR GDP
Pg
Pkp
Ras GTP Shoc2
Dp
GTP
Desmoplakin
PKC-α Ca2+
Ras Raf assembly
Shoc2 P
Mek
P
Erk IF
ER
Differentiation
Nucleus
Figure 3. Signaling roles of the desmosome. The desmosome has been linked to signaling pathways that regulate
biological mechanisms such as wound healing, proliferation, differentiation, and apoptosis. Here we summarize
signaling mechanisms that promote epidermal differentiation and proper desmosome assembly or remodeling.
location to the nucleus interferes with b-cate- skin abnormalities but still allows normal heart
nin signaling and promotes adipogenic/fibrot- development (Cabral et al. 2010). Further, only
ic transcriptional pathways in a Dp knockout keratoderma and not heart defects are observed
mouse model (Garcia-Gras et al. 2006). Itis spec- in a conditional Pg knockout mouse model
ulated that Pg nuclear functions may also ac- where Pg nuclear localization cannot occur
count for defects in hair follicles, which leads (Li et al. 2012). In spite of the fact that alterations
to the wooly hair seen in some patients (MacRae in Wnt/b-catenin signaling are not observed
et al. 2006). A Pg truncation mutation leads to in this model, alterations in cell proliferation,

Press
J.L. Johnson et al.
Pemphigus Arrhythmogenic right ventricular Striate palmoplantar keratoderma

cardiomyopathy (ARVC) (SPPK)
Autoimmune against Mutations in

Mutations in
Dsg1,3 DSG1
DSG2, DSC2, PKP2, JUP, DSP
Mutated dsg1 gene
Truncated dsg1 mRNA
Dsg1,3
Disruption of
Dsc
Fibrofatty tissue
area composita Truncated dsg1 protein
replacement
formation degraded
Decrease in total Dsg1 protein
Internalization EGFR and PKC

Decrease in Erbin
signaling Loss of electrical sequestering Shoc2
conductivity/ventricular
arrhythmia
p38/MAPK pErk
Differentiation (K10, Lor)
Reduced Rho
signaling Sudden cardiac death
Hyperkeratosis affecting
palms and soles
p.S132X
Control
SPPK
Dsg1
DAPI
Epidermal fragility
blistering Dermis Dermis
Figure 4. Diseases associated with the desmosome. Many diseases causing epidermal and cardiac tissue impair-
ment are linked to improper desmosome functioning. Highlighted here are three different diseases (Pemphigus,
ARVC, and SPPK) that are caused by autoimmunity and genetic mutations. It is important to note that SPPK is
also caused by mutations in the genes of Plakoglobin and Desmoplakin (JUP and DSP). We have summarized the
molecular pathway of SPPK caused by mutations in DSG1, and show tissue staining from SPPK patients
harboring mutant Dsg1 ( p.S132X) (Harmon et al. 2013).
apoptosis, differentiation, and the epidermal signaling deficits may contribute to ARVC path-
immune system occur. It is possible that other ogenesis.
signaling pathways previously associated with
loss of Pg (e.g., EGFR) (Pan et al. 2007) or
REGULATION OF DESMOSOME DYNAMICS,
Src/Rho signaling (Todorovic et al. 2010; Fran-
REMODELING, AND TURNOVER
zen et al. 2012) contribute to these changes.
It is notable that another armadillo protein, Although cell adhesion is imperative for main-
Pkp2, is the most commonly mutated target in taining tissue integrity, adhesive contacts cannot
ARVC (Kowalczyk and Green 2013). Alterations remain static during processes like epider-
in RhoA and PKC-a signaling occur follow- mal development, differentiation, wound heal-
ing Pkp2 knockdown in keratinocytes (Godsel ing, and apoptosis. Desmosomes are degraded
et al. 2010), raising the possibility that similar or internalized in response to EGFR signal-

Press
ing, ADAM sheddases, matrix metalloproteases this phosphodeficient Dp mediates strong

(MMPs), caspases, and kallikrein peptidases desmosome adhesion (Hobbs et al. 2011).
(Bektas et al. 2010; Green et al. 2010; Kowalczyk PKC-a is a calcium-dependent kinase and is
and Green 2013). The ubiquitin proteosome thus sensitive to changes in intracellular calci-
may reduce cell adhesion by keeping Dp from um homeostasis. Supporting the importance of
cell contacts. Proteosome inhibition stabilizes this relationship for desmosome assembly, the
Dp at keratinocyte borders and strengthens endoplasmic reticulum calcium pump Serca2,
cell – cell contacts (Loffek et al. 2012). However, which is mutated in a skin disorder known as
it remains to be seen whether the proteosome Darier’s disease, regulates intercellular adhesive
regulates desmosomal adhesion under physio- strength through PKC-a (Hobbs et al. 2011).
logical conditions. Serca2 deficient cells show reduced PKC-a
Desmosomes in adult tissues show a unique and Dp movement to the membrane, but con-
property termed “hyperadhesion,” character- stitutively active PKC-a rescues this defect.
ized by enhanced stability and adhesive strength Desmosome-cytoskeleton interactions are
even in the context of extracellular calcium de- important for regulating desmosome assembly
pletion. Desmosomes become hyperadhesive state and turnover and, in turn, desmosomal
during mouse embryonic development before components control cytoskeletal distribution
embryo implantation; however, migration of and function. Desmosomes are well known for
the trophectoderm requires loss of hyperadhe- their role in anchoring keratin intermediate fil-
sion (Kimura et al. 2012) as does the remodeling aments to sites of cell adhesion, but they are also
that occurs during wound healing (Thomason subject to regulation by keratins, which keep
et al. 2010). PKC-a is the predominant regulator PKC-a-mediated Dp phosphorylation in check
of the switch between hyperadhesion and cal- to stabilize desmosomes at the plasma mem-
cium dependence (Wallis et al. 2000). Desmo- brane (Kroger et al. 2013). The actin cytoskele-
somes remain hyperadhesive in PKC-a null ton and associated contractile signaling also en-
animals and re-epithelialization after wounding gages in a reciprocal functional relationship with
is delayed. In chronic human wounds PKC-a desmosomes. Actin regulates desmosome dy-
remains cytoplasmic and desmosomes do not namics during desmosomal plaque assembly
become hyperadhesive (Thomason et al. 2012). and wound healing (Godsel et al. 2010; Roberts
In addition to its role in converting mature et al. 2011). In turn, desmosome molecules reg-
desmosomes to a more dynamic form compat- ulate contractile signaling through Pkp2, which
ible with epithelial remodeling, PKC-a regu- recruits active RhoA at cell – cell interfaces to
lates the dynamics of desmosome assembly drive actin reorganization and actin-depen-
(Fig. 3). PKC inhibition decreases desmosome dent desmosome assembly (Godsel et al. 2010).
assembly at the leading edge in scratch wound Dsg3 also dictates cytoskeletal organization and
assays (Roberts et al. 2011), and Dp transloca- cell migration through regulation of the Rho
tion from the cytoplasm to the plasma mem- GTPases Rac-1 and Cdc42 (Tsang et al. 2010,
brane depends on PKC (Sheu et al. 1989; Bass- 2012a). Finally, desmosomes help remodel the
Zubek et al. 2008). Dp’s responsiveness to PKC microtubule cytoskeleton during epidermal
is due in part to its association with the arma- stratification. Dp, together with the centrosomal
dillo protein Pkp2, which serves as a scaffold for protein ninein, facilitates redistribution of radi-
PKC-a. Data support a model whereby loss of ally oriented microtubules to the cell cortex.
Pkp2 results in failure of PKC to phosphorylate Cortical microtubules in the suprabasal epider-
Dp and failure of Dp to incorporate into des- mis recruit myosin II to aid formation of the
mosomes owing to tight association with inter- tight junction barrier (Lechler and Fuchs 2007;
mediate filaments (Bass-Zubek et al. 2008). A Sumigray and Lechler 2012). Microtubule-asso-
mutation in the Dp carboxyl terminus at S2849 ciated proteins such as Lis1, Ndel1, and CLIP70
prevents its phosphorylation and delays assem- regulate desmosome stability and their loss leads
bly into junctions. However, once incorporated, to decreased expression of desmosomal compo-

Press
J.L. Johnson et al.
nents (Sumigray et al. 2011; Sumigray and Lech- reduced symptoms arising from desmosomal
ler 2011). Thus, desmosomes engage the cyto- diseases, reduced epidermal damage after envi-
skeleton in a more general way than previous- ronmental exposure, and prevention of carcino-
ly recognized, contributing to cytoarchitectural genesis. These include EGFR inhibitors, histone
remodeling during differentiation. deacetylase inhibitors, cholinergic agonists, or
tyrosine phosphatase inhibitors like sodium
pervanadate (Nguyen et al. 2003; Lorch et al.
PHARMACOLOGICAL APPROACHES TO
2004; Garrod et al. 2008; Simpson et al. 2010;
REGULATING DESMOSOMAL EXPRESSION
Aktary and Pasdar 2012; Johnson et al. 2014).
AND STABILITY
Rescuing adhesive defects and improving out-
EMERGING AREAS IN DESMOSOME
comes for desmosomal diseases would be ad-
BIOLOGY: OUTLOOK FOR THE FUTURE
vantageous to human health. To that end, sever-
al pharmacologic strategies have been explored Over the past decade we have come to appreci-
to regulate desmosome stability in epidermal ate desmosomes as both critical regulators of
cells. Treatment of organotypic epidermal mod- intercellular adhesive strength and modulators
els with retinoic acid results in normalization of of intracellular signaling cascades (Green and
desmosome appearance after a low dose of UVB Gaudry 2000; Thomason et al. 2010; Kowalczyk
exposure (Chouinard and Rouabhia 1999) but and Green 2013). At the same time, cell junc-
retinoic acid is more frequently reported to tions have emerged as transducers of mechan-
down-regulate expression of desmosomal com- ical signals that affect stem cell maintenance,
ponents in human skin (Humphries et al. 1998; tissue morphogenesis, and differentiation.
Wanner et al. 1999; Kim et al. 2011). A serine Whereas the mechanical importance of the des-
palmitoyltransferase inhibitor (ISP-I) increases mosome-intermediate filament network is well

the number of corneodesmosomes leading to a accepted, the field of mechanotransduction has
thicker stratum corneum and less transepider- mainly focused on the role of actin-associated
mal water loss (Mizukoshi et al. 2011). contacts. The adherens junction protein a-cat-
Glucocorticoids are used together with im- enin undergoes conformational change in re-
munosuppressive therapies to treat pemphigus sponse to mechanical cues to affect recruitment
(Frydman and Fairley 2011). Dsg3 and Dsc2 of proteins such as vinculin and EPLIN. These
contain retinoic acid and glucocorticoid re- changes affect junctional remodeling in re-
sponsive elements in their promoters (Silos sponse to shear in endothelial cells and estab-
et al. 1996; Marsden et al. 1997), so use of these lishment of barrier in simple epithelial cells
agents may alter desmosomal component tran- (Twiss and de Rooij 2013). Desmosomal cadher-
scription. In support of this, mice lacking the ins and plaque proteins may play similar roles in
glucocorticoid receptor show reduced numbers response to mechanical stresses experienced by
of desmosomes (Bayo et al. 2008). A novel treat- skin and heart. Development of sensors that
ment option for pemphigus may also be emerg- track mechanosensitive conformation changes
ing, as cross-linking of Dsg3 using a topically in desmosome molecules will begin to shed light
applied peptide on mice reduces skin blistering. on the potential activity of desmosomes in me-
The peptide stabilizes Dsg3 by blocking auto- chanotransduction.
antibody-mediated interference of Dsg3 trans- The critical role desmosomes play in estab-
interaction, reduces p38/MAPK activation, and lishing the epidermal barrier raises the possibil-
allows stabilization of keratins (Spindler et al. ity that their loss of function may activate path-
2013). It is unknown whether a similar pep- ways contributing to inflammation and allergy.
tide-mediated cross-linking of Dsg1 would re- Indeed, a new syndrome caused by homozygous
duce blistering in pemphigus foliaceus. Other mutations in Dsg1 was recently described with
drugs that increase desmosomal protein expres- symptoms including severe dermatitis, multi-
sion and strengthen desmosomes may lead to ple allergies and metabolic wasting (SAM syn-

Press
drome). Dsg1 deficiency associated with in- sity Skin Disease Research Center (Parent Grant
creases in allergy-related cytokines strongly sug- NIAMS 5P30 AR057216-04). N.A.N. has been
gesting that allergy can result from desmosomal supported by an NIH/NCI Ruth L. Kirschstein
disruption (Samuelov et al. 2013). Further, mice Training grant through Northwestern Univer-
deficient in envoplakin, periplakin, and the cell sity’s Robert H. Lurie Comprehensive Cancer
envelope protein involucrin show a reduction in Center (T32 CA080621) “Training Program in
the protease inhibitor serpin1b, delayed degra- Oncogenesis and Developmental Biology.”
dation of desmoglein 1 and corneodesmosin,
and alterations in the T-cell population resem-
bling atopic dermatitis (Sevilla et al. 2007). A REFERENCES
variant of the protease inhibitor LEKT1 increas- Adams MJ, Reichel MB, King IA, Marsden MD, Greenwood
es expression of the proallergic cytokine thymic MD, Thirlwell H, Arnemann J, Buxton RS, Ali RR. 1998.
Characterization of the regulatory regions in the human
stromal lymphopoietin (TSLP), a predisposing desmoglein genes encoding the pemphigus foliaceous
factor to atopic dermatitis (Descargues et al. and pemphigus vulgaris antigens. Biochem J 329: 165–
2006; Hovnanian 2013). Finally, there exists 174.
an inflammatory subtype of generalized peeling Aho S, Rothenberger K, Tan EM, Ryoo YW, Cho BH,
McLean WH, Uitto J. 1999. Human periplakin: Genomic
skin syndrome (PSS) in which patients show organization in a clonally unstable region of chromo-
chronic exfoliation of the stratum corneum at- some 16p with an abundance of repetitive sequence ele-
tributable to mutations in corneodesmosin ments. Genomics 56: 160–168.
(Oji et al. 2010). Corneodesmosin mutations Aigner K, Descovich L, Mikula M, Sultan A, Dampier B,
Bonne S, van Roy F, Mikulits W, Schreiber M, Brabletz
also confer susceptibility to psoriasis indicating T, et al. 2007. The transcription factor ZEB1 (dEF1) re-
that intact desmosome-mediated epidermal presses Plakophilin 3 during human cancer progression.
barrier function is important for protection FEBS Lett 581: 1617–1624.
against the disease (Chang et al. 2003, 2006). Aijaz S, Sanchez-Heras E, Balda MS, Matter K. 2007. Regu-
lation of tight junction assembly and epithelial morpho-
The extent to which desmosomal disruption genesis by the heat shock protein Apg-2. BMC Cell Biol
and changes in downstream signaling pathways 8: 49.
drive atopy, inflammation, or psoriasis is un- Aktary Z, Pasdar M. 2012. Plakoglobin: Role in tumorigen-
esis and metastasis. Int J Cell Biol 2012: 189521.
known, but these emerging associations provide
Allen E, Yu QC, Fuchs E. 1996. Mice expressing a mutant
compelling basis for future work to directly link desmosomal cadherin exhibit abnormalities in desmo-
loss of desmosome function to these systemic somes, proliferation, and epidermal differentiation.
and collectively common disorders. J Cell Biol 133: 1367–1382.
Amagai M, Stanley JR. 2012. Desmoglein as a target in skin
disease and beyond. J Invest Dermatol 132: 776– 784.
ACKNOWLEDGMENTS Amagai M, Klaus-Kovtun V, Stanley JR. 1991. Autoantibod-
ies against a novel epithelial cadherin in pemphigus vul-
We have attempted to be comprehensive in our garis, a disease of cell adhesion. Cell 67: 869 –877.
references throughout this review but regret that Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS.
1991. Chromosomal assignment of the human genes
because of space constraints we have been un- coding for the major proteins of the desmosome junc-
able to reference all of the researchers working tion, desmoglein DGI (DSG), desmocollins DGII/III
in the desmosome field. We thank Jennifer (DSC), desmoplakins DPI/II (DSP), and plakoglobin
DPIII (JUP). Genomics 10: 640– 645.
Koetsier and Drs. Robert Lavker, Lisa Godsel, Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S,
and Robert Harmon for helpful comments on Basso C, Thiene G, Tsatsopoulou A, Protonotarios N,
the manuscript. K.J.G. is supported by National McKenna WJ, et al. 2009. A new diagnostic test for ar-
rhythmogenic right ventricular cardiomyopathy. N Engl J
Institutes of Health Grants RO1 AR041836, R37 Med 360: 1075– 1084.
AR043380, and R01 CA122151, by a grant from Bailey CK, Mittal MK, Misra S, Chaudhuri G. 2012. High
the Leducq Foundation, and by the Joseph motility of triple-negative breast cancer cells is due to
L. Mayberry Senior Endowment. J.L.J. is sup- repression of plakoglobin gene by metastasis modulator
protein SLUG. J Biol Chem 287: 19472– 19486.
ported by a Dermatology Foundation Research
Baron S, Hoang A, Vogel H, Attardi LD. 2012. Unimpaired
Career Development Award and a Pilot and Fea- skin carcinogenesis in desmoglein 3 knockout mice. PLoS
sibility grant through the Northwestern Univer- ONE 7: e50024.

Press
J.L. Johnson et al.
Bass-Zubek AE, Hobbs RP, Amargo EV, Garcia NJ, Hsieh Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ. 2002.
SN, Chen X, Wahl JK III, Denning MF, Green KJ. 2008. Protein binding and functional characterization of pla-
Plakophilin 2: A critical scaffold for PKC-a that regulates kophilin 2. Evidence for its diverse roles in desmosomes
intercellular junction assembly. J Cell Biol 181: 605 –613. and beta-catenin signaling. J Biol Chem 277: 10512–
Bayerl C, Taake S, Moll I, Jung EG. 1995. Characterization of 10522.
sunburn cells after exposure to ultraviolet light. Photo- Chidgey M, Brakebusch C, Gustafsson E, Cruchley A, Hail
dermatol Photoimmunol Photomed 11: 149– 154. C, Kirk S, Merritt A, North A, Tselepis C, Hewitt J, et al.
Bayo P, Sanchis A, Bravo A, Cascallana JL, Buder K, Tuck- 2001. Mice lacking desmocollin 1 show epidermal fragil-
ermann J, Schutz G, Perez P. 2008. Glucocorticoid recep- ity accompanied by barrier defects and abnormal differ-
tor is required for skin barrier competence. Endocrinology entiation. J Cell Biol 155: 821 –832.
149: 1377–1388. Chouinard N, Rouabhia M. 1999. Effects of all-trans retino-
Bazzi H, Christiano AM. 2007. Broken hearts, woolly hair, ic acid on UVB-irradiated human skin substitute. J Cell
and tattered skin: When desmosomal adhesion goes Physiol 181: 14–23.
awry. Curr Opin Cell Biol 19: 515– 520. Chu YS, Thomas WA, Eder O, Pincet F, Perez E, Thiery JP,
Bazzi H, Demehri S, Potter CS, Barber AG, Awgulewitsch A, Dufour S. 2004. Force measurements in E-cadherin-me-
Kopan R, Christiano AM. 2009. Desmoglein 4 is regulat- diated cell doublets reveal rapid adhesion strengthened by
ed by transcription factors implicated in hair shaft dif- actin cytoskeleton remodeling through Rac and Cdc42.
ferentiation. Differentiation 78: 292 –300. J Cell Biol 167: 1183–1194.
Beaudry VG, Jiang D, Dusek RL, Park EJ, Knezevich S, Ridd Chun MG, Hanahan D. 2010. Genetic deletion of the des-
K, Vogel H, Bastian BC, Attardi LD. 2010. Loss of the mosomal component desmoplakin promotes tumor mi-
p53/p63 regulated desmosomal protein Perp promotes croinvasion in a mouse model of pancreatic neuroendo-
tumorigenesis. PLoS Genet 6: e1001168. crine carcinogenesis. PLoS Genet 6: e1001120.
Bektas M, Jolly P, Rubenstein DS. 2010. Apoptotic pathways Cirillo N, Al-Jandan BA. 2013. Desmosomal adhesion and
in pemphigus. Dermatol Res Pract 2010: 456841. pemphigus vulgaris: The first half of the story. Cell Com-
Bonne S, van Hengel J, van Roy F. 1998. Chromosomal mun Adhes 20: 1– 10.
mapping of human armadillo genes belonging to the Cowley CM, Simrak D, Marsden MD, King IA, Arnemann J,
pp120(ctn)/plakophilin subfamily. Genomics 51: 452– Buxton RS. 1997a. AYAC contig joining the desmocollin
454. and desmoglein loci on human chromosome 18 and or-
Brennan D, Mahoney MG. 2009. Increased expression of dering of the desmocollin genes. Genomics 42: 208– 216.
Dsg2 in malignant skin carcinomas: A tissue-microarray Cowley CM, Simrak D, Spurr NK, Arnemann J, Buxton RS.
based study. Cell Adh Migr 3: 148 –154. 1997b. The plakophilin 1 (PKP1) and plakoglobin (JUP)
Brennan D, Hu Y, Joubeh S, Choi YW, Whitaker-Menezes D, genes map to human chromosomes 1q and 17, respec-
O’Brien T, Uitto J, Rodeck U, Mahoney MG. 2007. Supra- tively. Hum Genet 100: 486 –488.
basal Dsg2 expression in transgenic mouse skin confers a
Cui T, Chen Y, Yang L, Knosel T, Zoller K, Huber O, Petersen
hyperproliferative and apoptosis-resistant phenotype to
I. 2011. DSC3 expression is regulated by pp53, and meth-
keratinocytes. J Cell Sci 120: 758 –771.
ylation of DSC3 DNA is a prognostic marker in human
Brennan D, Hu Y, Medhat W, Dowling A, Mahoney MG. colorectal cancer. Br J Cancer 104: 1013–1019.
2010. Superficial dsg2 expression limits epidermal blister
Delva E, Tucker DK, Kowalczyk AP. 2009. The desmosome.
formation mediated by pemphigus foliaceus antibodies
and exfoliative toxins. Dermatol Res Pract 2010: 410278. Cold Spring Harb Perspect Biol 1: a002543.
Byrne C, Tainsky M, Fuchs E. 1994. Programming gene Denning MF, Guy SG, Ellerbroek SM, Norvell SM, Kowalc-
expression in developing epidermis. Development 120: zyk AP, Green KJ. 1998. The expression of desmoglein
2369– 2383. isoforms in cultured human keratinocytes is regulated
by calcium, serum, and protein kinase C. Exp Cell Res
Cabral RM, Liu L, Hogan C, Dopping-Hepenstal PJ, Winik
239: 50–59.
BC, Asial RA, Dobson R, Mein CA, Baselaga PA, Mellerio
JE, et al. 2010. Homozygous mutations in the 50 region of Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-
the JUP gene result in cutaneous disease but normal heart Hautier J, D’Alessio M, Ishida-Yamamoto A, Bodemer C,
development in children. J Invest Dermatol 130: 1543– Zambruno G, Hovnanian A. 2006. Corneodesmosomal
1550. cadherins are preferential targets of stratum corneum
trypsin- and chymotrypsin-like hyperactivity in Nether-
Chang YT, Tsai SF, Lee DD, Shiao YM, Huang CY, Liu HN,
Wang WJ, Wong CK. 2003. A study of candidate genes for ton syndrome. J Invest Dermatol 126: 1622–1632.
psoriasis near HLA-C in Chinese patients with psoriasis. Dong JT, Chen C. 2009. Essential role of KLF5 transcrip-
Br J Dermatol 148: 418– 423. tion factor in cell proliferation and differentiation and its
Chang YT, Chou CT, Shiao YM, Lin MW, Yu CW, Chen CC, implications for human diseases. Cell Mol Life Sci 66:
Huang CH, Lee DD, Liu HN, Wang WJ, et al. 2006. Pso- 2691–2706.
riasis vulgaris in Chinese individuals is associated with Dubash AD, Koetsier JL, Amargo EV, Najor NA, Harmon
PSORS1C3 and CDSN genes. Br J Dermatol 155: 663 – RM, Green KJ. 2013. The GEF Bcr activates RhoA/MAL
669. signaling to promote keratinocyte differentiation via des-
Charpentier E, Lavker RM, Acquista E, Cowin P. 2000. Pla- moglein-1. J Cell Biol 202: 653– 666.
koglobin suppresses epithelial proliferation and hair Dusek RL, Attardi LD. 2011. Desmosomes: New perpetra-
growth in vivo. J Cell Biol 149: 503–520. tors in tumour suppression. Nat Rev Cancer 11: 317– 323.

Press
Dusek RL, Getsios S, Chen F, Park JK, Amargo EV, Cryns VL, Green KJ, Gaudry CA. 2000. Are desmosomes more than
Green KJ. 2006. The differentiation-dependent desmoso- tethers for intermediate filaments? Nat Rev Mol Cell Biol
mal cadherin desmoglein 1 is a novel caspase-3 target that 1: 208– 216.
regulates apoptosis in keratinocytes. J Biol Chem 281: Green KJ, Simpson CL. 2007. Desmosomes: New perspec-
3614– 3624. tives on a classic. J Invest Dermatol 127: 2499–2515.
Dusek RL, Godsel LM, Chen F, Strohecker AM, Getsios S, Green KJ, Getsios S, Troyanovsky S, Godsel LM. 2010. In-
Harmon R, Muller EJ, Caldelari R, Cryns VL, Green KJ. tercellular junction assembly, dynamics, and homeosta-
2007. Plakoglobin deficiency protects keratinocytes from sis. Cold Spring Harb Perspect Biol 2: a000125.
apoptosis. J Invest Dermatol 127: 792 –801.
Groot KR, Sevilla LM, Nishi K, DiColandrea T, Watt FM.
Elias PM, Matsuyoshi N, Wu H, Lin C, Wang ZH, Brown BE, 2004. Kazrin, a novel periplakin-interacting protein as-
Stanley JR. 2001. Desmoglein isoform distribution affects sociated with desmosomes and the keratinocyte plasma
stratum corneum structure and function. J Cell Biol 153: membrane. J Cell Biol 166: 653– 659.
243–249.
Hanakawa Y, Matsuyoshi N, Stanley JR. 2002. Expression of
Eshkind L, Tian Q, Schmidt A, Franke WW, Windoffer R, desmoglein 1 compensates for genetic loss of desmoglein
Leube RE. 2002. Loss of desmoglein 2 suggests essential 3 in keratinocyte adhesion. J Invest Dermatol 119: 27–31.
functions for early embryonic development and prolifer-
ation of embryonal stem cells. Eur J Cell Biol 81: 592 –598. Hardman MJ, Liu K, Avilion AA, Merritt A, Brennan K,
Garrod DR, Byrne C. 2005. Desmosomal cadherin mis-
Ferone G, Mollo MR, Thomason HA, Antonini D, Zhou H,
expression alters b-catenin stability and epidermal dif-
Ambrosio R, De Rosa L, Salvatore D, Getsios S, van Bok-
ferentiation. Mol Cell Biol 25: 969 –978.
hoven H, et al. 2013. p63 control of desmosome gene
expression and adhesion is compromised in AEC syn- Harmon RM, Simpson CL, Johnson JL, Koetsier JL, Dubash
drome. Hum Mol Genet 22: 531– 543. AD, Najor NA, Sarig O, Sprecher E, Green KJ. 2013. Des-
moglein-1/Erbin interaction suppresses ERK activation
Franzen CA, Todorovic V, Desai BV, Mirzoeva S, Yang XJ,
to support epidermal differentiation. J Clin Invest 123:
Green KJ, Pelling JC. 2012. The desmosomal armadillo
1556–1570.
protein plakoglobin regulates prostate cancer cell adhe-
sion and motility through vitronectin-dependent Src sig- Hartlieb E, Kempf B, Partilla M, Vigh B, Spindler V, Waschke
naling. PLoS ONE 7: e42132. J. 2013. Desmoglein 2 is less important than desmoglein 3
for keratinocyte cohesion. PLoS ONE 8: e53739.
Frydman AS, Fairley JA. 2011. New and innovative interven-
tions in the management of pemphigus. G Ital Dermatol Henkler F, Strom M, Mathers K, Cordingley H, Sullivan K,
Venereol 146: 211– 224. King I. 2001. Trangenic misexpression of the differentia-
Funakoshi S, Ezaki T, Kong J, Guo RJ, Lynch JP. 2008. Re- tion-specific desmocollin isoform 1 in basal keratino-
pression of the desmocollin 2 gene expression in human cytes. J Invest Dermatol 116: 144 –149.
colon cancer cells is relieved by the homeodomain tran- Hobbs RP, Amargo EV, Somasundaram A, Simpson CL,
scription factors Cdx1 and Cdx2. Mol Cancer Res 6: Prakriya M, Denning MF, Green KJ. 2011. The calcium
1478– 1490. ATPase SERCA2 regulates desmoplakin dynamics and
Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, intercellular adhesive strength through modulation of
Degenstein L, Fuchs E. 1998. Desmoplakin is required PKC-a signaling. FASEB J 25: 990 –1001.
early in development for assembly of desmosomes and Hofmann I, Casella M, Schnolzer M, Schlechter T, Spring H,
cytoskeletal linkage. J Cell Biol 143: 2009–2022. Franke WW. 2006. Identification of the junctional plaque
Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, protein plakophilin 3 in cytoplasmic particles containing
Schneider MD, Khoury DS, Marian AJ. 2006. Suppres- RNA-binding proteins and the recruitment of plakophi-
sion of canonical Wnt/b-catenin signaling by nuclear lins 1 and 3 to stress granules. Mol Biol Cell 17: 1388–
plakoglobin recapitulates phenotype of arrhythmogen- 1398.
ic right ventricular cardiomyopathy. J Clin Invest 116: Hovnanian A. 2013. Netherton syndrome: Skin inflamma-
2012– 2021. tion and allergy by loss of protease inhibition. Cell Tissue
Gardel ML, Kasza KE, Brangwynne CP, Liu J, Weitz DA. Res 351: 289–300.
2008. Chapter 19: Mechanical response of cytoskeletal Humphries JD, Parry EJ, Watson RE, Garrod DR, Griffiths
networks. Methods Cell Biol 89: 487–519. CE. 1998. All-trans retinoic acid compromises desmo-
Garrod DR, Fisher C, Smith A, Nie Z. 2008. Pervanadate some expression in human epidermis. Br J Dermatol
stabilizes desmosomes. Cell Adh Migr 2: 161– 166. 139: 577–584.
Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Du- Ihrie RA, Attardi LD. 2005. A new Perp in the lineup: Link-
sek RL, Cornwell M, Green KJ. 2009. Desmoglein 1-de- ing p63 and desmosomal adhesion. Cell Cycle 4: 873–
pendent suppression of EGFR signaling promotes epi- 876.
dermal differentiation and morphogenesis. J Cell Biol Johnson JL, Koetsier JL, Sirico A, Agidi AT, Antonini D,
185: 1243–1258. Missero C, Green KJ. 2014. The desmosomal protein
Godsel LM, Dubash AD, Bass-Zubek AE, Amargo EV, Kless- desmoglein 1 aids recovery of epidermal differentiation
ner JL, Hobbs RP, Chen X, Green KJ. 2010. Plakophilin 2 after acute ultraviolet light exposure. J Invest Dermatol
couples actomyosin remodeling to desmosomal plaque doi: 10.1038/jid.2014.124.
assembly via RhoA. Mol Biol Cell 21: 2844– 2859. Kalantari-Dehaghi M, Anhalt GJ, Camilleri MJ, Chernyav-
Grando SA. 2012. Pemphigus autoimmunity: Hypotheses sky AI, Chun S, Felgner PL, Jasinskas A, Leiferman KM,
and realities. Autoimmunity 45: 7 –35. Liang L, Marchenko S, et al. 2013. Pemphigus vulgaris

Press
J.L. Johnson et al.
autoantibody profiling by proteomic technique. PLoS rier disruption and hair-follicle degeneration related to
ONE 8: e57587. desmosome dysfunction. J Cell Sci 122: 2699–2709.
Kaz AM, Luo Y, Dzieciatkowski S, Chak A, Willis JE, Upton Leitner L, Shaposhnikov D, Mengel A, Descot A, Julien S,
MP, Leidner RS, Grady WM. 2012. Aberrantly methylat- Hoffmann R, Posern G. 2011. MAL/MRTF-A controls
ed PKP1 in the progression of Barrett’s esophagus to migration of non-invasive cells by upregulation of cyto-
esophageal adenocarcinoma. Genes Chromosomes Cancer skeleton-associated proteins. J Cell Sci 124: 4318– 4331.
51: 384 –393. Li D, Turi TG, Schuck A, Freedberg IM, Khitrov G, Blumen-
Kenchegowda D, Harvey SA, Swamynathan S, Lathrop KL, berg M. 2001. Rays and arrays: The transcriptional pro-
Swamynathan SK. 2012. Critical role of Klf5 in regulating gram in the response of human epidermal keratinocytes
gene expression during post-eyelid opening maturation to UVB illumination. FASEB J 15: 2533– 2535.
of mouse corneas. PLoS ONE 7: e44771. Li D, Zhang W, Liu Y, Haneline LS, Shou W. 2012. Lack of
Khapare N, Kundu ST, Sehgal L, Sawant M, Priya R, Gosavi plakoglobin in epidermis leads to keratoderma. J Biol
P, Gupta N, Alam H, Karkhanis M, Naik N, et al. 2012. Chem 287: 10435–10443.
Plakophilin3 loss leads to an increase in PRL3 levels Lin S, Gordon K, Kaplan N, Getsios S. 2010. Ligand target-
promoting K8 dephosphorylation, which is required ing of EphA2 enhances keratinocyte adhesion and differ-
for transformation and metastasis. PLoS ONE 7: e38561. entiation via desmoglein 1. Mol Biol Cell 21: 3902–3914.
Kim MY, Lee SE, Chang JY, Kim SC. 2011. Retinoid induces Loffek S, Bruckner-Tuderman L, Magin TM. 2012. Involve-
the degradation of corneodesmosomes and downregula- ment of the ubiquitin-proteasome system in the stabili-
tion of corneodesmosomal cadherins: Implications on zation of cell-cell contacts in human keratinocytes. Exp
the mechanism of retinoid-induced desquamation. Ann Dermatol 21: 791–793.
Dermatol 23: 439– 447.
Lopez-Pajares V, Yan K, Zarnegar BJ, Jameson KL, Khavari
Kimura TE, Merritt AJ, Lock FR, Eckert JJ, Fleming TP, PA. 2013. Genetic pathways in disorders of epidermal
Garrod DR. 2012. Desmosomal adhesiveness is develop- differentiation. Trends Genet 29: 31–40.
mentally regulated in the mouse embryo and modulated
during trophectoderm migration. Dev Biol 369: 286– Lorch JH, Klessner J, Park JK, Getsios S, Wu YL, Stack MS,
297. Green KJ. 2004. Epidermal growth factor receptor inhi-
bition promotes desmosome assembly and strengthens
Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. 2009.
intercellular adhesion in squamous cell carcinoma cells.
EGFR and ADAMs cooperate to regulate shedding and
J Biol Chem 279: 37191– 37200.
endocytic trafficking of the desmosomal cadherin des-
moglein 2. Mol Biol Cell 20: 328 –337. Maatta A, Ruhrberg C, Watt FM. 2000. Structure and regu-
lation of the envoplakin gene. J Biol Chem 275: 19857–
Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaugh-
19865.
nessy R, Mahoney MG, Levy M, Montagutelli X, Ahmad
W, Aita VM, et al. 2003. Desmoglein 4 in hair follicle MacRae CA, Birchmeier W, Thierfelder L. 2006. Arrhyth-
differentiation and epidermal adhesion: Evidence from mogenic right ventricular cardiomyopathy: Moving to-
inherited hypotrichosis and acquired pemphigus vulga- ward mechanism. J Clin Invest 116: 1825–1828.
ris. Cell 113: 249 –260. Mannan T, Jing S, Foroushania SH, Fortune F, Wan H. 2011.
Kolegraff K, Nava P, Helms MN, Parkos CA, Nusrat A. 2011. RNAi-mediated inhibition of the desmosomal cadherin
Loss of desmocollin-2 confers a tumorigenic phenotype (desmoglein 3) impairs epithelial cell proliferation. Cell
to colonic epithelial cells through activation of Akt/b- Prolif 44: 301 –310.
catenin signaling. Mol Biol Cell 22: 1121– 1134. Mao X, Nagler AR, Farber SA, Choi EJ, Jackson LH, Leifer-
Koulu L, Kusumi A, Steinberg MS, Klaus-Kovtun V, Stanley man KM, Ishii N, Hashimoto T, Amagai M, Zone JJ,
JR. 1984. Human autoantibodies against a desmosomal et al. 2010. Autoimmunity to desmocollin 3 in pemphi-
core protein in pemphigus foliaceus. J Exp Med 160: gus vulgaris. Am J Pathol 177: 2724–2730.
1509– 1518. Mao X, Sano Y, Park JM, Payne AS. 2011. p38 MAPK acti-
Kowalczyk AP, Green KJ. 2013. Structure, function, and vation is downstream of the loss of intercellular adhesion
regulation of desmosomes. Prog Mol Biol Transl Sci 116: in pemphigus vulgaris. J Biol Chem 286: 1283– 1291.
95–118. Mao X, Li H, Sano Y, Gaestel M, Mo Park J, Payne AS. 2013.
Kroger C, Loschke F, Schwarz N, Windoffer R, Leube RE, MAPKAP kinase 2 (MK2)-dependent and independent
Magin TM. 2013. Keratins control intercellular adhesion models of blister formation in pemphigus vulgaris. J In-
involving PKC-a-mediated desmoplakin phosphoryla- vest Dermatol 134: 68–76.
tion. J Cell Biol 201: 681 –692. Marsden MD, Collins JE, Greenwood MD, Adams MJ,
Lebeau S, Masouye I, Berti M, Augsburger E, Saurat JH, Fleming TP, Magee AI, Buxton RS. 1997. Cloning and
Borradori L, Fontao L. 2005. Comparative analysis of transcriptional analysis of the promoter of the human
the expression of ERBIN and Erb-B2 in normal human type 2 desmocollin gene (DSC2). Gene 186: 237 –247.
skin and cutaneous carcinomas. Br J Dermatol 152: 1248– Matsuda M, Hoshino T, Yamashita Y, Tanaka K, Maji D, Sato
1255. K, Adachi H, Sobue G, Ihn H, Funasaka Y, et al. 2013.
Lechler T, Fuchs E. 2007. Desmoplakin: An unexpected Prevention of UVB radiation-induced epidermal damage
regulator of microtubule organization in the epidermis. by expression of heat shock protein 70. J Biol Chem 285:
J Cell Biol 176: 147 –154. 5848–5858.
Leclerc EA, Huchenq A, Mattiuzzo NR, Metzger D, Cham- Merritt AJ, Berika MY, Zhai W, Kirk SE, Ji B, Hardman MJ,
bon P, Ghyselinck NB, Serre G, Jonca N, Guerrin M. 2009. Garrod DR. 2002. Suprabasal desmoglein 3 expression in
Corneodesmosin gene ablation induces lethal skin-bar- the epidermis of transgenic mice results in hyperprolif-

Press
eration and abnormal differentiation. Mol Cell Biol 22: Potter E, Braun S, Lehmann U, Brabant G. 2001. Molecular
5846– 5858. cloning of a functional promoter of the human plakoglo-
Miralles F, Posern G, Zaromytidou AI, Treisman R. 2003. bin gene. Eur J Endocrinol 145: 625 –633.
Actin dynamics control SRF activity by regulation of its Rawlings A, Harding C, Watkinson A, Banks J, Ackerman C,
coactivator MAL. Cell 113: 329–342. Sabin R. 1995. The effect of glycerol and humidity on
Mizukoshi K, Matsumoto K, Hirose R, Fujita T, Ishida-Ya- desmosome degradation in stratum corneum. Arch Der-
mamoto A, Iizuka H. 2011. Effects of serine palmitoyl- matol Res 287: 457 –464.
transferase inhibitor ISP-I on the stratum corneum of Reczek EE, Flores ER, Tsay AS, Attardi LD, Jacks T. 2003.
intact mouse skin. Biol Pharm Bull 34: 1383– 1389. Multiple response elements and differential p53 binding
control Perp expression during apoptosis. Mol Cancer Res
Mucke N, Kreplak L, Kirmse R, Wedig T, Herrmann H, Aebi
1: 1048–1057.
U, Langowski J. 2004. Assessing the flexibility of interme-
diate filaments by atomic force microscopy. J Mol Biol Roberts BJ, Pashaj A, Johnson KR, Wahl JK III. 2011. Des-
335: 1241–1250. mosome dynamics in migrating epithelial cells requires
the actin cytoskeleton. Exp Cell Res 317: 2814–2822.
Murakami T, Fujimoto M, Ohtsuki M, Nakagawa H. 2001.
Roemer K. 2012. Notch and the p53 clan of transcription
Expression profiling of cancer-related genes in human
factors. Adv Exp Med Biol 727: 223 –240.
keratinocytes following non-lethal ultraviolet B irradia-
tion. J Dermatol Sci 27: 121– 129. Ruhrberg C, Hajibagheri MA, Parry DA, Watt FM. 1997.
Periplakin, a novel component of cornified envelopes
Nachat R, Cipolat S, Sevilla LM, Chhatriwala M, Groot KR, and desmosomes that belongs to the plakin family and
Watt FM. 2009. KazrinE is a desmosome-associated li- forms complexes with envoplakin. J Cell Biol 139: 1835–
prin that colocalises with acetylated microtubules. J Cell 1849.
Sci 122: 4035–4041.
Rundhaug JE, Hawkins KA, Pavone A, Gaddis S, Kil H, Klein
Nava P, Laukoetter MG, Hopkins AM, Laur O, Gerner- RD, Berton TR, McCauley E, Johnson DG, Lubet RA,
Smidt K, Green KJ, Parkos CA, Nusrat A. 2007. Desmo- et al. 2005. SAGE profiling of UV-induced mouse skin
glein-2: A novel regulator of apoptosis in the intestinal squamous cell carcinomas, comparison with acute UV
epithelium. Mol Biol Cell 18: 4565–4578. irradiation effects. Mol Carcinog 42: 40– 52.
Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y, Ryan KR, Lock FE, Heath JK, Hotchin NA. 2012. Plakoglo-
Grando SA. 2003. Keratinocyte acetylcholine receptors bin-dependent regulation of keratinocyte apoptosis by
regulate cell adhesion. Life Sci 72: 2081–2085. Rnd3. J Cell Sci 125: 3202–3209.
Nguyen B, Dusek RL, Beaudry VG, Marinkovich MP, Attardi Saito M, Stahley SN, Caughman CY, Mao X, Tucker DK,
LD. 2009. Loss of the desmosomal protein perp enhances Payne AS, Amagai M, Kowalczyk AP. 2012. Signaling de-
the phenotypic effects of pemphigus vulgaris autoanti- pendent and independent mechanisms in pemphigus
bodies. J Invest Dermatol 129: 1710– 1718. vulgaris blister formation. PLoS ONE 7: e50696.
Ning S, Hahn GM. 1994. Formation of tight junctions and Samady L, Faulkes DJ, Budhram-Mahadeo V, Ndisang D,
desmosomes protects MDCK cells against hyperthermic Potter E, Brabant G, Latchman DS. 2006. The Brn-3b
killing. J Cell Physiol 160: 249– 254. POU family transcription factor represses plakoglobin
Oji V, Eckl KM, Aufenvenne K, Natebus M, Tarinski T, Ac- gene expression in human breast cancer cells. Int J Cancer
118: 869–878.
kermann K, Seller N, Metze D, Nurnberg G, Folster-Holst
R, et al. 2010. Loss of corneodesmosin leads to severe skin Samuelov L, Sarig O, Harmon RM, Rapaport D, Ishida-
barrier defect, pruritus, and atopy: Unraveling the peel- Yamamoto A, Isakov O, Koetsier JL, Gat A, Goldberg I,
ing skin disease. Am J Hum Genet 87: 274– 281. Bergman R, et al. 2013. Desmoglein 1 deficiency results in
severe dermatitis, multiple allergies and metabolic wast-
Oshiro MM, Watts GS, Wozniak RJ, Junk DJ, Munoz-Ro- ing. Nat Genet 45: 1244–1248.
driguez JL, Domann FE, Futscher BW. 2003. Mutant p53
Sato J, Denda M, Nakanishi J, Koyama J. 1998. Dry condi-
and aberrant cytosine methylation cooperate to silence
tion affects desquamation of stratum corneum in vivo.
gene expression. Oncogene 22: 3624–3634.
J Dermatol Sci 18: 163–169.
Owens P, Bazzi H, Engelking E, Han G, Christiano AM,
Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C,
Wang XJ. 2008. Smad4-dependent desmoglein-4 expres-
Gridley T, Hudson LG. 2005. Developmental transcrip-
sion contributes to hair follicle integrity. Dev Biol 322: tion factor slug is required for effective re-epithelializa-
156–166. tion by adult keratinocytes. J Cell Physiol 202: 858–866.
Pan H, Gao F, Papageorgis P, Abdolmaleky HM, Faller DV, Sesto A, Navarro M, Burslem F, Jorcano JL. 2002. Analysis of
Thiagalingam S. 2007. Aberrant activation of g-catenin the ultraviolet B response in primary human keratino-
promotes genomic instability and oncogenic effects dur- cytes using oligonucleotide microarrays. Proc Natl Acad
ing tumor progression. Cancer Biol Ther 6: 1638– 1643. Sci 99: 2965– 2970.
Parker HR, Li Z, Sheinin H, Lauzon G, Pasdar M. 1998. Sevilla LM, Nachat R, Groot KR, Klement JF, Uitto J, Djian P,
Plakoglobin induces desmosome formation and epider- Maatta A, Watt FM. 2007. Mice deficient in involucrin,
moid phenotype in N-cadherin-expressing squamous envoplakin, and periplakin have a defective epidermal
carcinoma cells deficient in plakoglobin and E-cadherin. barrier. J Cell Biol 179: 1599–1612.
Cell Motil Cytoskeleton 40: 87– 100. Sevilla LM, Nachat R, Groot KR, Watt FM. 2008. Kazrin
Petrof G, Mellerio JE, McGrath JA. 2012. Desmosomal gen- regulates keratinocyte cytoskeletal networks, intercellular
odermatoses. Br J Dermatol 166: 36– 45. junctions and differentiation. J Cell Sci 121: 3561–3569.

Press
J.L. Johnson et al.
Sheu HM, Kitajima Y, Yaoita H. 1989. Involvement of pro- Tachikawa T, Kohno Y, Matsui Y, Yoshiki S. 1986. In vitro
tein kinase C in translocation of desmoplakins from cy- early changes in intercellular junctions by treatment with
tosol to plasma membrane during desmosome formation a chemical carcinogen. Carcinogenesis 7: 885–892.
in human squamous cell carcinoma cells grown in low to Tada H, Hatoko M, Tanaka A, Kuwahara M, Muramatsu T.
normal calcium concentration. Exp Cell Res 185: 176 – 2000. Expression of desmoglein I and plakoglobin in skin
190. carcinomas. J Cutan Pathol 27: 24–29.
Shim JS, Kim DH, Kwon HJ. 2004. Plakoglobin is a new Teh MT, Parkinson EK, Thurlow JK, Liu F, Fortune F, Wan H.
target gene of histone deacetylase in human fibrosarcoma 2011. A molecular study of desmosomes identifies a des-
HT1080 cells. Oncogene 23: 1704–1711. moglein isoform switch in head and neck squamous cell
Silos SA, Tamai K, Li K, Kivirikko S, Kouba D, Christiano carcinoma. J Oral Pathol Med 40: 67–76.
AM, Uitto J. 1996. Cloning of the gene for human pem- Thomason HA, Scothern A, McHarg S, Garrod DR. 2010.
phigus vulgaris antigen (desmoglein 3), a desmosomal Desmosomes: Adhesive strength and signalling in health
cadherin. Characterization of the promoter region and and disease. Biochem J 429: 419–433.
identification of a keratinocyte-specific cis-element. J Biol Thomason HA, Cooper NH, Ansell DM, Chiu M, Merrit AJ,
Chem 271: 17504– 17511. Hardman MJ, Garrod DR. 2012. Direct evidence that
Simpson CL, Kojima S, Cooper-Whitehair V, Getsios S, PKC-a positively regulates wound re-epithelialization:
Green KJ. 2010. Plakoglobin rescues adhesive defects in- Correlation with changes in desmosomal adhesiveness.
duced by ectodomain truncation of the desmosomal cad- J Pathol 227: 346– 356.
herin desmoglein: 1. Implications for exfoliative toxin- Todorovic V, Desai BV, Patterson MJ, Amargo EV, Dubash
mediated skin blistering. Am J Pathol 177: 2921– 2937. AD, Yin T, Jones JC, Green KJ. 2010. Plakoglobin regu-
Simrak D, Cowley CM, Buxton RS, Arnemann J. 1995. Tan- lates cell motility through Rho- and fibronectin-depen-
dem arrangement of the closely linked desmoglein genes dent Src signaling. J Cell Sci 123: 3576–3586.
on human chromosome 18. Genomics 25: 591 –594. Tokonzaba E, Chen J, Cheng X, Den Z, Ganeshan R, Muller
Smith C, Zhu K, Merritt A, Picton R, Youngs D, Garrod D, EJ, Koch PJ. 2013. Plakoglobin as a regulator of desmo-
Chidgey M. 2004. Regulation of desmocollin gene expres- collin gene expression. J Invest Dermatol 133: 2732–2740.
sion in the epidermis: CCAAT/enhancer-binding pro- Tsang SM, Liu L, Teh MT, Wheeler A, Grose R, Hart IR,
teins modulate early and late events in keratinocyte dif- Garrod DR, Fortune F, Wan H. 2010. Desmoglein 3, via
ferentiation. Biochem J 380: 757– 765. an interaction with E-cadherin, is associated with activa-
Sonnenberg A, Liem RK. 2007. Plakins in development and tion of Src. PLoS ONE 5: e14211.
disease. Exp Cell Res 313: 2189–2203. Tsang SM, Brown L, Gadmor H, Gammon L, Fortune F,
Spindler V, Waschke J. 2011. Role of Rho GTPases in des- Wheeler A, Wan H. 2012a. Desmoglein 3 acting as an
mosomal adhesion and pemphigus pathogenesis. Ann upstream regulator of Rho GTPases, Rac-1/Cdc42 in
Anat 193: 177– 180. the regulation of actin organisation and dynamics. Exp
Spindler V, Rotzer V, Dehner C, Kempf B, Gliem M, Radeva Cell Res 318: 2269–2283.
M, Hartlieb E, Harms GS, Schmidt E, Waschke J. 2013. Tsang SM, Brown L, Lin K, Liu L, Piper K, O’Toole EA, Grose
Peptide-mediated desmoglein 3 cross-linking prevents R, Hart IR, Garrod DR, Fortune F, et al. 2012b. Non-
pemphigus vulgaris autoantibody-induced skin blister- junctional human desmoglein 3 acts as an upstream reg-
ing. J Clin Invest 123: 800–811. ulator of Src in E-cadherin adhesion, a pathway possibly
Steinert PM, Marekov LN. 1999. Initiation of assembly of involved in the pathogenesis of pemphigus vulgaris. J
the cell envelope barrier structure of stratified squamous Pathol 227: 81–93.
epithelia. Mol Biol Cell 10: 4247–4261. Twiss F, de Rooij J. 2013. Cadherin mechanotransduction in
Sumigray KD, Lechler T. 2011. Control of cortical microtu- tissue remodeling. Cell Mol Life Sci 70: 4101–4116.
bule organization and desmosome stability by centroso- Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruy-
mal proteins. Bioarchitecture 1: 221 –224. neel E, Andersen H, Tulchinsky E, Van Roy F, Berx G.
Sumigray KD, Lechler T. 2012. Desmoplakin controls mi- 2005. SIP1/ZEB2 induces EMT by repressing genes of
crovilli length but not cell adhesion or keratin organiza- different epithelial cell-cell junctions. Nucleic Acids Res
tion in the intestinal epithelium. Mol Biol Cell 23: 792 – 33: 6566–6578.
799. Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D.
Sumigray KD, Chen H, Lechler T. 2011. Lis1 is essential 2000. The a isoform of protein kinase C is involved in
for cortical microtubule organization and desmosome signaling the response of desmosomes to wounding in
stability in the epidermis. J Cell Biol 194: 631–642. cultured epithelial cells. Mol Biol Cell 11: 1077–1092.
Swamynathan S, Kenchegowda D, Piatigorsky J. 2011. Reg- Walsh R, Blumenberg M. 2011. Eph-2B, acting as an extra-
ulation of corneal epithelial barrier function by Kruppel- cellular ligand, induces differentiation markers in epider-
like transcription factor 4. Invest Ophthalmol Vis Sci 52: mal keratinocytes. J Cell Physiol 227: 2330–2340.
1762– 1769. Wan H, South AP, Hart IR. 2007. Increased keratino-
Szegedi A, Payer E, Czifra G, Toth BI, Schmidt E, Kovacs L, cyte proliferation initiated through downregulation of
Blumberg PM, Biro T. 2009. Protein kinase C isoenzymes desmoplakin by RNA interference. Exp Cell Res 313:
differentially regulate the differentiation-dependent ex- 2336–2344.
pression of adhesion molecules in human epidermal ker- Wang Y, Amagai M, Minoshima S, Sakai K, Green KJ, Nish-
atinocytes. Exp Dermatol 18: 122– 129. ikawa T, Shimizu N. 1994. The human genes for desmo-

Press
gleins (DSG1 and DSG3) are located in a small region on function from stabilizing cell adhesion to promoting cell
chromosome 18q12. Genomics 20: 492– 495. proliferation. J Cell Sci 126: 1832–1844.
Wanner R, Wolff B, Glowacki F, Kolde G, Wittig B. 1999. The Wong MP, Cheang M, Yorida E, Coldman A, Gilks CB,
loss of desmosomes after retinoic acid treatment results Huntsman D, Berean K. 2008. Loss of desmoglein 1 ex-
in an apparent inhibition of HaCaT keratinocyte differ- pression associated with worse prognosis in head and
entiation. Arch Dermatol Res 291: 346– 353. neck squamous cell carcinoma patients. Pathology 40:
Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G, 611 –616.
Drenckhahn D. 2006. Inhibition of Rho A activity causes Yamazaki S, Uchiumi A, Katagata Y. 2012. Hsp40 regulates
pemphigus skin blistering. J Cell Biol 175: 721 –727. the amount of keratin proteins via ubiquitin-proteasome
pathway in cultured human cells. Int J Mol Med 29: 165–
White FH, Gohari K. 1984. A qualitative ultrastructural
168.
study of the intercellular spaces between epithelial cells
treated in vivo with DMBA. J Oral Pathol 13: 231 –243. Yang L, Chen Y, Cui T, Knosel T, Zhang Q, Albring KF, Huber
O, Petersen I. 2012. Desmoplakin acts as a tumor sup-
Whittock NV, Bower C. 2003. Genetic evidence for a novel pressor by inhibition of the Wnt/b-catenin signaling
human desmosomal cadherin, desmoglein 4. J Invest pathway in human lung cancer. Carcinogenesis 33:
Dermatol 120: 523– 530. 1863–1870.
Wilanowski T, Caddy J, Ting SB, Hislop NR, Cerruti L, Yin T, Getsios S, Caldelari R, Kowalczyk AP, Muller EJ, Jones
Auden A, Zhao LL, Asquith S, Ellis S, Sinclair R, et al. JC, Green KJ. 2005. Plakoglobin suppresses keratinocyte
2008. Perturbed desmosomal cadherin expression in motility through both cell –cell adhesion-dependent
grainy head-like 1-null mice. EMBO J 27: 886– 897. and-independent mechanisms. Proc Natl Acad Sci 102:
Wolf A, Rietscher K, Glass M, Huttelmaier S, Schutkowski 5420–5425.
M, Ihling C, Sinz A, Wingenfeld A, Mun A, Hatzfeld M. Yong AA, Tey HL. 2012. Paraneoplastic pemphigus. Aus-
2013. Insulin signaling via Akt2 switches plakophilin 1 tralas J Dermatol 54: 241 –250.

Desmosome Signaling

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Desmosome Signaling

Încărcat de

Drepturi de autor:

Formate disponibile

Downloaded from http://perspectivesinmedicine.cshlp.

org/ on December 4, 2014 - Published by Cold Spring Harbor Laboratory

Desmosomes: Regulators of Cellular Signaling and Adhesion in

Cold Spring Harb Perspect Med 2014; doi: 10.1101/cshperspect.a015297

Subject Collection The Skin and Its Diseases

For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/

Desmosomes: Regulators of Cellular Signaling

Jodi L. Johnson1,2, Nicole A. Najor1, and Kathleen J. Green1,2

esmosomes are intercellular junctions that er tissue-specific desmosome proteins include

Editors: Anthony E. Oro and Fiona M. Watt

J.L. Johnson et al.

2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Plakin Armadillo Cadherin

the “wrong” layer can lead to alterations in pro- TRANSCRIPTIONAL REGULATION

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 3

J.L. Johnson et al.

al protein expression in keratinocytes, such as factors to desmosomal component promoters

4 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Table 1. Transcriptional regulators of desmosomal components, representative upstream signaling pathways

lymphocytes, muscle cells

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 5

J.L. Johnson et al.

6 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Lef-1 repression of Dsc3 2013

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 7

J.L. Johnson et al.

Dp Methylation Progression of lung cancer Yang et al. 2012

8 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 9

J.L. Johnson et al.

10 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Attardi 2011) suggesting that desmosomal com- victronectin-dependent or fibronectin-depen-

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 11

J.L. Johnson et al.

12 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 13

J.L. Johnson et al.

Pemphigus Arrhythmogenic right ventricular Striate palmoplantar keratoderma

Autoimmune against Mutations in

Truncated dsg1 mRNA

Decrease in total Dsg1 protein

Internalization EGFR and PKC

14 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

ing, ADAM sheddases, matrix metalloproteases this phosphodeficient Dp mediates strong

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 15

J.L. Johnson et al.

palmitoyltransferase inhibitor (ISP-I) increases mosome-intermediate filament network is well

16 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 17

J.L. Johnson et al.

18 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease

Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297 19

J.L. Johnson et al.

20 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015297

Desmosomes in Epidermal Health and Disease