ライフサイエンスコーパス: Dsg2

1 he epithelial junction protein desmoglein 2 (DSG2).

2 3 fibre knob (HAd3K) and human desmoglein 2 (DSG2).

3 ngle known desmosomal protein, Desmoglein 2 (Dsg2).

4 zheimer's disease risk factor, desmoglein 2 (DSG2).

5 alizes to lipid rafts along with full-length Dsg2.

6 n tumors from transgenic mice overexpressing Dsg2.

7 to highly conserved residues within PKP2 and DSG2.

8 but not PG(WT) to desmosome proteins DSP and DSG2.

9 ructural details of the Ad3 interaction with DSG2.

10 g2 cleavage product and internalized pool of Dsg2.

11 nerated an antibody, AH12.2, that recognizes Dsg2.

12 e pair of desmosomal glycoproteins, Dsc2 and Dsg2.

13 hr170) are required for the translocation of Dsg2.

14 n the subcellular distribution of endogenous Dsg2.

15 of activated p38 MAPK with Dsg3 but not with Dsg2.

16 ually, ablated or reduced Ad knob binding to DSG2.

17 which might facilitate the interaction with DSG2.

18 identify variants with increased affinity to DSG2.

19 DGV (212 [40%] PKP2, 160 [30%] DSP, 97 [18%] DSG2, 34 [6%] DSC2) and 30 of 533 (6%) double DGVs.

20 e found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular a

21 ith the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in mali

22 sion levels of 2 genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/beta-catenin

23 Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal

24 ce were prepared with cardiomyocyte-specific DSG2 ablation.

25 However, the mechanisms by which Dsg2 activates these signaling pathways and the relative

26 Subsequent derepression of DSG2 after intravasation and release of hypoxic stress w

27 Mice carrying 2 mutant DSG2 alleles coding for Dsg2 lacking part of the adhesiv

28 Interaction with DSG2 allows the virus not only to enter cells but also t

29 The other desmosomal genes (PKP2 and DSG2), along with TMEM43, showed SMVTs with left bundle

30 istribution was paralleled by an increase in Dsg2 and desmoplakin in the Triton-insoluble cell fracti

31 s demonstrate that the desmosomal cadherins, Dsg2 and Dsc1a, are involved in a direct Ca2+-dependent

32 rotein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation.

33 We demonstrate that Dsg2 and Dsc2 both exhibit microtubule-dependent transpo

34 emonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic

35 Mutations in DSP, JUP, PKP2, DSG2 and DSC2, encoding desmosomal proteins desmoplakin,

36 Crystal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding throug

37 n this study, we compared the involvement of Dsg2 and Dsg3 in the p38 MAPK-dependent regulation of ke

38 human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples.

39 , PKI166 blocked tyrosine phosphorylation of Dsg2 and plakoglobin following epidermal growth factor s

40 ion of the desmosomal cadherin desmoglein-2 (Dsg2) and characterized the role that palmitoylation of

41 red the assembly properties of desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2), which are widely express

42 The accumulated levels of desmoglein 2 (Dsg2) and desmocollin 2 increased 1.7-2.0-fold, and both

43 ne desmosomal cadherins termed desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) that affiliate with the u

44 oglobin, plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), respectively, cause ARV

45 the affected protein: desmosomal (DSP, PKP2, DSG2, and DSC2), nuclear membrane (LMNA and TMEM43), cyt

46 ive loss-of-function variants in PKP2, DSC2, DSG2, and DSP.

47 calized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within

48 bands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous

49 d CD46, structural details for Ad binding to DSG2 are still elusive.

50 Desmocollin-2 (Dsc2) and desmoglein-2 (Dsg2) are transmembrane cell adhesion proteins of desmos

51 oviruses use the epithelial junction protein DSG2 as a receptor for infection and lateral spread.

52 uman adenoviruses (HAdVs) uses desmoglein 2 (DSG2) as a receptor for infection.

53 he epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection.

54 Recently, we identified desmoglein 2 (DSG2) as the main receptor for a group of species B aden

55 A proteomic screen for Dsg2-associated proteins in intestinal epithelial cells

56 In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major prote

57 ere, we show that EGFR inhibition stabilizes Dsg2 at intercellular junctions by interfering with its

58 per, we show that the DUR of Dsg2 stabilized Dsg2 at the cell surface by inhibiting its internalizati

59 on of the desmosomal cadherin, desmoglein 2 (Dsg2), at cell-cell interfaces accompanied by inhibition

60 We show that Dsg2 but not another desmosomal cadherin, Dsc2, is cleav

61 , blocked shedding and depleted internalized Dsg2, but less so E-cadherin, in highly invasive SCC68 c

62 The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulat

63 of hypoxia-inducible genes, HIF1a repressed DSG2 by recruitment of the polycomb repressive complex 2

64 m sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor rec

65 d in single spreading cells, indicating that Dsg2 can exert its effects on cell spreading independent

66 GDNF concentrations accompanied by a loss of DSG2, changes of the intermediate filament system, and i

67 M10 siRNA enhanced accumulation of a 100-kDa Dsg2 cleavage product and internalized pool of Dsg2.

68 delayed, and a pool of the non-palmitoylated Dsg2 co-localized with lysosomal markers.

69 ane in Dsg3 knockout cells, we conclude that Dsg2 compensates for Dsg3 loss of function.

70 We propose that loss of Dsg2 compromises adhesion, and that this is a major path

71 The genetic DSG2 constellations encountered are compatible with loss

72 Sequence analysis revealed that Dsg2 contains a putative Cav-1-binding motif.

73 We report that mutations in DSG2 contribute to the development of ARVD/C.

74 t competitively inhibits galectin binding to Dsg2, decreased intercellular adhesion in intestinal epi

75 DSG2-deficient and RET-deficient Caco2 cells revealed th

76 Dsg2-deficient cells demonstrated a compensatory increas

77 iated loss of Dsc2 restored proliferation in Dsg2-deficient cells.

78 Dsg2 transport, resulting in the assembly of Dsg2-deficient junctions with minimal impact on distribu

79 implicated the Rap GEF PDZ-GEF2 in mediating Dsg2-dependent cell spreading.

80 ol cells, the response to MMP-inhibition was Dsg2-dependent.

81 ess, because subsequent targeting of Dsg3 in Dsg2-depleted cells led to drastically enhanced keratino

82 chanisms, we examined whether heart-specific Dsg2 depletion triggers cardiomyopathy.

83 We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molec

84 cancer cell lines, JO-1 mediated cleavage of DSG2 dimers and activated intracellular signaling pathwa

85 acking the desmosomal cadherin Desmoglein-2 (Dsg2) displayed a significant increase in spreading area

86 mbling the Cav-1 scaffolding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with

87 The shed DSG2 domain can be detected in cell culture supernatant

88 Dsg2 downregulation inhibited epidermal growth factor re

89 analyses to determine the role of AC-linked DSG2 downregulation on SN biology and assess cardiac sym

90 AC-linked DSG2 downregulation primarily affect sympathetic neurons

91 Consistently, virus-assisted DSG2 downregulation replicated, in PC12-derived SNs, the

92 quencing of the desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP) from 3 arrhythmogenic right ventric

93 coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands di

94 f 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and wer

95 e-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or

96 alloprotease (MMP)-dependent shedding of the Dsg2 ectodomain and tyrosine phosphorylation of its cyto

97 Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of

98 , BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C,

99 This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor m

100 these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism b

101 Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and

102 Gal3 bound to N-linked beta-galactosides in Dsg2 extracellular domain and co-sedimented with caveoli

103 dividuals had mutations in PKP2, DSP, and/or DSG2 genes.

104 When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, gr

105 is elevated in Dsg2 knockout cells, and that Dsg2 harnesses Rap1 and downstream TGFB signaling to inf

106 These mice expressed human DSG2 (hDSG2) at a level and in a pattern similar to thos

107 acellular domain of DSG2, thereby disrupting DSG2 homodimers between epithelial cells.

108 Dsc2 and Dsg2 IFs were stronger in superficial layers, but Dsc3 a

109 Molecular assays showed that SNs express DSG2, implying that DSG2-mutation carriers would harbour

110 Knockdown of DSG2 in APOE varepsilon3/4 induced neurons effectively r

111 Overexpression of Dsg2 in ASZ001 cells, a Ptc1(-/-) BCC cell line, induced

112 These data have identified a novel role for Dsg2 in controlling cell spreading, providing insight in

113 6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release.

114 s key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevate

115 (+/lacZ) mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1(+/lacZ) mice) or

116 Overexpression of Dsg2 increased EV release and mitogenic content includin

117 We found that the DSG2-interacting domain(s) within Ad3 is formed by sever

118 inical symptoms associated with infection by DSG2-interacting HAdVs and provide a rationale for using

119 We confirmed this pathway with a second DSG2-interacting serotype, Ad14, and its recently emerge

120 e of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by car

121 his structure reveals that the ectodomain of Dsg2 is flexible even in the calcium-bound state and, on

122 We have shown previously that Dsg2 is less important for keratinocyte cohesion compare

123 00 solubility assays demonstrate that mutant Dsg2 is more soluble than wild-type protein.

124 The observations show that the presence of Dsg2 is not essential for late heart morphogenesis and f

125 Additionally, we observed that Dsg2 is proteolytically processed; resulting in a 95-kDa

126 Desmoglein-2 (Dsg2) is a desmosomal cadherin that is aberrantly expres

127 desmosomal junctional protein desmoglein 2 (DSG2) is a hallmark in the pathogenesis of inflammatory

128 We recently discovered that desmoglein 2 (DSG2) is a receptor for human adenovirus species B serot

129 yopathy linked to mutations in desmoglein-2 (DSG2) is frequent and leads to a left-dominant form of t

130 ning pool revealed that Dsg3, in contrast to Dsg2, is present in relevant amounts in the unbound pool

131 veals a unique stoichiometry of 1:1 and 2:1 (DSG2: knob trimer) not previously observed for other HAd

132 We show that Rap1 activity is elevated in Dsg2 knockout cells, and that Dsg2 harnesses Rap1 and do

133 Because DSG2 knockouts die during early embryogenesis, mice were

134 ce carrying 2 mutant DSG2 alleles coding for Dsg2 lacking part of the adhesive EC1-EC2 domains presen

135 Although mutant Dsg2 localizes to endogenous desmosomes, there is a sign

136 The desmosomal cadherin desmoglein 2 (Dsg2) localizes to the intercalated disc coupling adjace

137 nerated transgenic mice containing the human DSG2 locus.

138 We hypothesized that Dsg2 may mediate cell-matrix adhesion via control of Rap

139 ce led to impaired IEB function with reduced DSG2 mediated by p38 MAPK-dependent phosphorylation of c

140 urther delineate the mechanism that leads to DSG2-mediated epithelial junction opening in cells expos

141 to the cell borders, resulting in increased DSG2-mediated intercellular adhesion via the RET recepto

142 When cardiomyocytes differentiated from Dsg2 (mut/mut) embryonic stem cells (ES-CMs) were challe

143 In addition, pretreatment of Dsg2 (mut/mut) ES-CMs with an AIF-mimetic peptide, mirro

144 We detected calcium (Ca(2+)) overload in Dsg2 (mut/mut) hearts, which induced calpain-1 (CAPN1) a

145 Hearts from exercised Dsg2 (mut/mut) mice were depleted of calpastatin (CAST),

146 we showed that homozygous Dsg2 mutant mice (Dsg2 (mut/mut)), a model of ACM, die prematurely during

147 Hearts of Dsg2(mut/mut) mice expressed markedly increased levels o

148 Cardiac SNs isolated from Dsg2(mut/mut) neonatal mice, prior to the establishment

149 SNs, the phenotypic alterations displayed by Dsg2(mut/mut) primary neurons, corroborating that AC-lin

150 pathetic innervation in desmoglein-2 mutant (Dsg2(mut/mut)) mice.

151 (homozygous knock-in of mutant desmoglein-2 [Dsg2(mut/mut)]) that recapitulates the cardiac manifesta

152 Here, we showed that homozygous Dsg2 mutant mice (Dsg2 (mut/mut)), a model of ACM, die p

153 We also show that a Dsg2 mutant, V977fsX1006, identified in arrhythmogenic r

154 showed that SNs express DSG2, implying that DSG2-mutation carriers would harbour the mutant protein

155 Desmoglein 2 gene (DSG2) mutations cause arrhythmogenic cardiomyopathy (AC)

156 Dsc2.myc and Dsg2.myc assembled efficiently into desmosomes in every

157 of 198 subjects (7%), including DSP (n = 4), DSG2 (n = 5), DSC2 (n = 3), and junctional plakoglobin (

158 ing desmoplakin (DSP) (n = 6), desmoglein-2 (DSG2) (n = 5), plakophilin-4 (PKP4) (n = 1), and desmoco

159 c desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to e

160 han swap, a central interaction mechanism of DSG2 on the basis of structural data.

161 nificantly change the fiber knob affinity to DSG2 or the intracellular signaling and DSG2 shedding in

162 a cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP.

163 enic variant in a desmosome gene (PKP2, DSP, DSG2, or DSC2) were identified through the Geisinger MyC

164 haracterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured

165 echanism is the maintenance of desmoglein-2 (DSG2) positive tight junctions between malignant cells t

166 ADAM9 and 15 silencing also impaired Dsg2 processing, supporting the idea that this desmosoma

167 complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells.

168 interfering RNA-mediated down-regulation of Dsg2 protected epithelial cells from apoptosis.

169 Dsg2 protein expression was reduced below 3% in the hear

170 f human colon cancers demonstrated increased Dsg2 protein expression.

171 e possibility that accumulation of truncated Dsg2 protein interferes with desmosome assembly and/or m

172 nal fragment of Dsg2 regulates apoptosis and Dsg2 protein levels.

173 The increase in Dsg2 protein was in part due to the inhibition of matrix

174 In the absence of functional Gal3, Dsg2 protein was internalized from the plasma membrane a

175 Interestingly, Dsg2 proteolytic products are elevated in vivo in skin t

176 overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1(+/lacZ) mice) or the superficial epidermis (In

177 acZ) mice) or the superficial epidermis (Inv-Dsg2/Ptc1(+/lacZ) mice) resulted in increased spontaneou

178 ver, we report that a C-terminal fragment of Dsg2 regulates apoptosis and Dsg2 protein levels.

179 studies highlight a novel mechanism by which Dsg2 regulates IEC apoptosis driven by cysteine protease

180 mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote canc

181 r, these data suggest that palmitoylation of Dsg2 regulates protein transport to the plasma membrane.

182 that this is a major pathogenic mechanism in DSG2-related and probably other desmosome-related ACs.

183 ted JO4, a recombinant protein that binds to DSG2 resulting in the transient opening of junctions in

184 hesized that GDNF is involved in the loss of DSG2, resulting in impaired IEB function as seen in IBD.

185 e blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2,

186 y to DSG2 or the intracellular signaling and DSG2 shedding in epithelial cancer cells.

187 Furthermore, in contrast to depletion of Dsg2, siRNA-mediated silencing of Dsg3 induced p38 MAPK

188 In this paper, we show that the DUR of Dsg2 stabilized Dsg2 at the cell surface by inhibiting i

189 lding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with the integrity of epith

190 The Dsg2 structure has an excellent fit with the electron to

191 Forced dimerization of a Dsg2 tail lacking the DUR led to decreased internalizati

192 ar cardiomyopathy patients, led to a loss of Dsg2 tail self-association and underwent rapid endocytos

193 in turn, cleaves the extracellular domain of DSG2 that links epithelial cells together.

194 the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than t

195 xtamembrane (intracellular anchor) domain of Dsg2 that, when mutated, eliminate its palmitoylation.

196 ntestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithel

197 the cleavage of the extracellular domain of DSG2, thereby disrupting DSG2 homodimers between epithel

198 irment of IEB function caused by the loss of DSG2 through p38 MAPK-dependent phosphorylation of cytok

199 lls revealed that GDNF specifically recruits DSG2 to the cell borders, resulting in increased DSG2-me

200 Interestingly, trafficking of the mutant Dsg2 to the cell surface was delayed, and a pool of the

201 Disruption of lipid rafts shifted Dsg2 to the non-raft fractions, leading to the accumulat

202 asma membrane accumulation without affecting Dsg2 trafficking.

203 studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no t

204 nctional interference with kinesin-1 blocked Dsg2 transport, resulting in the assembly of Dsg2-defici

205 yses that Ad3-K/S/Kn, through its binding to DSG2, triggered the transient opening of intercellular j

206 Ad3 binding to DSG2 triggers the transient opening of epithelial juncti

207 odomain of desmosomal cadherin desmoglein 2 (Dsg2), using a combination of small-angle X-ray scatteri

208 rimary neurons, corroborating that AC-linked Dsg2 variants may affect SNs.

209 The DSG2-W2A knock-in mouse model was analyzed by echocardio

210 This DSG2-W2A mutation abrogates the tryptophan swap, a centr

211 The DSG2-W2A mutation impaired binding on molecular level an

212 Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays

213 cally enhanced keratinocyte dissociation and Dsg2 was enhanced at the membrane in Dsg3 knockout cells

214 In vivo, Dsg2 was highly up-regulated in the head and neck SCCs,

215 This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1a (HIF1a).

216 s junctions, whereas only a minor portion of Dsg2 was seen in these areas in the parental cells.

217 eins, desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2) were expressed throughout, but Dsc3 and Dsg3 were

218 probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the car

219 Furthermore, the association of Dsg2 with Cav-1 may provide a mechanism for regulating m

220 Ad3-K/S/Kn bound to DSG2 with high affinity and blocked Ad3 infection.

221 Ad3 binds to DSG2 with its fiber knob domain and triggers intracellul

222 Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001