Introduction 1864 1963 1958 1962 1965 2007 1864 1920 1956 1978 1986 1982 1990 1974 2+ 1987 1988 1986b 1993 1991 1984 2000 1964 1982 1976 1995 1994a 1992 2007b 2002 2004b 2007 2007 2002 2006 2008a 2004 2003 2003 2006 2004 2007 2005 2006 2006 2006 The ultrastructure and composition of desmosomes 1958 1 2 1963 1958 1966 1 2007 2007 Fig. 1 EC cis trans IDP  Fig. 2 Ultrastructure of the desmosome. The electron micrograph of a keratinocyte desmosome shows the desmosomal plaque with inserting cytokeratin intermediate filaments as well as some fuzzy material within the extracellular space likely reflecting the extracellular domains of desmosomal cadherins  Desmosomes and desmosome-like junctions Adhering junctions are divided into two main forms: (1) desmosomes, which serve as anchoring structures for intermediate filaments to desmosomal cadherins, and (2) adherens junctions, which contain cell-type specific adhesion molecules from the cadherin super-family that are linked to the actin cytoskeleton. Both, desmosomes and adherens junctions can be found as constituents of more elaborated cell contact complexes. Moreover, chimeric cell contacts exist which share features of both adherens junctions and desmosomes. Junctional complexes 1963 Area composita 3 1958 3 1969 1969 2004 1997 2003 2006 2006 2007 2008 Fig. 3 GJ asterisk hash key  Complexus adhaerentes and meningeal junctions 2006 1993 1994 1998 2008 The desmosomal components Desmosomal cadherins 2+ 1993 2002 2004b 2000 1981 1984 1991 1991b 1991 1991 1986a 1995 1991a 1990 1994 1986a b 2003 2003 1997 1 2006 2002 2001 1998 2003 Table 1 Desmosome-associated diseases in humans and in transgenic mouse models Mouse model  Desmosomal component Human disease Inactivation Genetic alteration  – Dsg 1  1999   2002 Dsg 2  2006    1998 Dsg 3 –   2003 Dsg 4  2003    2001 Dsc 1 – – Dsc 2  2006 2006  2006 Dsc 3 –    1996 1999 1996 Plakoglobin     2000    1998 2001) Desmoplakin  2002   1999 1999      2000      2005 – Plakophilin 1   1997   2004 Plakophilin 2  2004  Bacterial toxins   1970 2000a b Dsg 1      Autoantibodies   1995 Dsg 1      1953 1984 1991   1982 1992 1999 Dsg 3   1953 1991 The structure of desmosomal cadherins 2007b 2002 1995 1995 2+ 1999 1994b 2003 1994 1994a 1991 2003 1993 2007b 2+ 2+ 1997 2007 1999 2007 2+ 2+ 2+  2007 2+ 2+ 2+ 2002 1991 Transinteraction mechanisms of desmosmal cadherins 1990 1998 2001 1998 2003 2001 2007 2007 2003 cis 2003 cis trans 2007 cis 2002 Homophilic and heterophilic binding of desmosomal cadherins 2002 1994b 2007 2005 2007 2003 2000 2007 1997 2002 2007 1996 1998 2001 2004a 2007 Armadillo family proteins From the Armadillo family, plakoglobin and plakophilins 1–3 are important components of desmosomes. Plakoglobin 1986 1989 1983 1995 1998 1996 1996 2003 2002 1997 1998 1 1996 1996 2004 2003 1999 2008a 2006 2000 2007 2006 2006 L, 2007a Plakophilins 1983 1994 1994 1999 1999 1998 1996 1997 1 2004 2003 2007 2000 2000 1999 2005 2007 1999 2006 2001 2007 2001 2007 Plakin family proteins 2007 1999 2001 1983 2007 1997 1998 1994b 2002 1990 1992 1 1996 1998 2000 2001 Diversity of desmosomes in different tissues and specific epithelial layers 1984 1986b 2002 2004b 2007 2007 2007 2006 2004 Some desmosomal components such as Dsg 2, Dsc 2 and the plaque proteins desmoplakin, plakoglobin and plakophilin 2 are ubiquitously expressed in all cells and tissues in which desmosomes are found. Plakophilin 3 is present in most simple epithelia except hepatocytes as well as in stratified epithelia, whereas plakophilin 1 is restricted to stratified and complex epithelia. In epithelia, the desmosomal cadherins show typical expression patterns. Simple epithelia and urothelium usually express Dsg 2 and Dsc 2 only. Apparently, exceptions are the additional presence of Dsg 1 in the mucosa of uterus, stomach, intestine and in epithelia of liver and pancreas as well as the expression of Dsc 1 in intestine and liver or Dsc 3 in stomach, prostate, salivary gland and urothelium. Dsg 4 has a unique tissue distribution in skin and several simple epithelia such as those present in pancreas, salivary glands, testis, prostate and hepatic epithelium. 4 2007b 2006 2007 5 2006 2007 2006 2006 Fig. 4 left BL SL GL CL Dsg Dsc Pkp PG DP  Fig. 5 a b Scale bar  2007 2001 2002 2007 2005 Desmosome assembly and disassembly 2004b 2007 2002 2004 2+  2+  1983 2+ 2+ 1983 1995 1988 1989 1989 2+ 2007 2000 2002 2000 2005 2007 2+ 2+ 2003 2004 1999 1997 2001 2003 1999 2001 2000 2002 2000 2001 Regulation of keratinocyte proliferation by desmosomal cadherins 2008a 2008a 2007 2006 2008a 2006 Desmosome-associated diseases 2007 Genetic diseases 1 2007 2007 2005 Genetic heart defects 2007 2004 2000 2006 2002 2006 2006 2007 2006 Genetic defects of skin and its appendages 2006 1999 2003 2005 1997 2001 Mutations in plaque proteins with involvement of various tissues 2000 1996 2000 1999 1999 2002 2005 2004 2005 2000 2004 Infectious diseases 1999 1983 2006 1 2000a 2002 2002 1970 2006 Pemphigus 1953 2005 2000 2006 6 2003 2004 1989 2006 2008 Fig. 6 PV a b c  Histology and autoantibody profile in pemphigus 2005 7 Fig. 7 a b Scale bar  1982 1976 2005 2005 1986 2005 2001 1997 2006 1984 2003 1999 1997 2003 1999 1999 2002 2003 2005 2005 2006 1995 1994a 1992 1991 1998 1984 1999 2000b 2005 2006 2008 2003 1989 2000c 2008 2004 2006 2000c 2006a 2000b 2000a 2000b 1995 1989 2001 2006 2004 The mechanisms underlying pemphigus skin blistering 8 Fig. 8 a b  Proteolytic cleavage of desmosomal cadherins 1978 2003 1983 2002 1996 1997 2007b 1995 2003 1983 1987 2003 1999 2000 2003 2007a d 2006 2007 2007a 2006 2007c 2008 2000a 2002 Direct inhibition of desmoglein binding 8 1991 1986a 1984 2007 2000 2003 2008 2008b 2001 trans 2007 2003 2002 1995 1995 1992 2006 2008b 2005 2000b 2005 2003 2007 2006 2007 2005 trans 2007 2003 Desmoglein compensation in pemphigus 2003 2004 2007 1998 2006 1999 9 10 2006 2005 2002 2007 Fig. 9 The desmoglein compensation hypothesis. Based on the different autoantibody profiles in PV and PF together with the findings that Dsg 3 is present in the deep epidermis only whereas Dsg 1 is primarily expressed in the superficial epidermis, the desmoglein compensation hypothesis has been proposed to explain the epidermal cleavage planes typical for PV and PF. According to this model, blistering in PF affects the superficial epidermis because Dsg 3 is present in the deep epidermis to compensate for the autoantibody-induced loss of Dsg 1 binding. In PV, epidermal involvement would occur only when autoantibodies against both Dsg 1 and Dsg 3 are present because Dsg 1 is found in all epidermal layers and could compensate for loss of Dsg 3 binding when antibodies to Dsg 3 are solely present  Fig. 10 a b arrows Scale bar  1999 2000 2007 1999 2006 1999 1996 1995 1993 2006 2007 2000 2006 1998 2007 2007 Signalling pathways in pemphigus and in desmosome disassembly 2+ 1995 8 2002 2006 2007 2005 2008a 2000 1985 1999 2006 2007a 2007 2008 2005 1990 2+ 2+ 1995 1999 1996 1997 1995 1999) 2+ 2005 2004 2007b 2007 p38MAPK 2006 2007b 2007a 2005 2006 2007a 2005 2007a 2006 2002 2007 2006 2001 2008 1999 2004 2000c 2007 2007 1985 2003 2005 2006 2006 2007 1999 2003 1994 2002 1997 Rho A GTPase 2005 2007 1999 2005 2005 2006 2007 2006 2006 2001 2004 1999 2006 2007a 1997 2005 2006 Plakoglobin 1999 2005 2001 2001 2003 2005 2005 2001 2007 2008a 2006 EGFR 2007a 2006 2006 2005 2008a 2001 2005 2006 2004 2007 Src 2007a 2007a 2004 2007b 2007 2004 Cholinergic receptors 2006a 2004b 2006 2004 2006a 2007b 2004a b 2002 Regulation of cell cycle and gene expression 2008a 2006 2007 2006 L  2007a 2008 2004a 2008 Apoptosis 1998 2003 2004a L  2005 2004 2007a 2005 2006 2004 2003 2004a b 2005 2005 2004 2005 2006 2004a b 2006 2001 2008 1999 2004 2000c 2007 2007 1985 2003 2005 2006 2006 2007a 2001 2005 2004a b 2001 Targets of signalling pathways in pemphigus 1999 1999 2006 2007 2000 2007 2006 2006 2007a 1985 Effects on desmosomes and adherens junctions 1999 1999 2006 2000 2006 2007a 2006 2007a 2007 2007a 2006 2006 1999 1999 1978 1977 2007b 2004a 2007b 2005 1978 1977 2000 2005 1999 2007 2006 2007 2006 2007 2008a 2006 2007b Effects on the cytoskeleton Alterations of the cytoskeleton have been described both in pemphigus skin lesions as well as in keratinocytes exposed to pemphigus autoantibodies,. These effects include dysorganization of cytokeratin filaments, the actin cytoskeleton as well as of microtubules. 2005 2001 2006 2007a 1992 1987 2006 1961 1964 2006 2005 2006 2007a 1986 2004 2007 2005 2007 2005 2006 1986 2006 1985 The role of the different mechanisms in blister formation 11 2005 2006 2007b 2001 2006 2006 2008a 2007 2003 2007 2005 Fig. 11 PLC PKC cdk 2 EGFR  11 2007 2007a 2007 2006 2+  2+  Concluding remarks 2006b