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Recently we reported that a desmosomal cadherin, desmoglein 3 (Dsg3), an autoantigen in pemphigus vulgaris (PV), associates with E\u2010cadherin and activates Src, which results in tyrosine phosphorylation of adherens junction proteins. However, the nature of such an interaction and its role in cell\u2013cell adhesion remain unclear. In this report, we provide direct evidence that it is the detergent\u2010soluble, non\u2010desmosomal Dsg3 that regulates the activity of Src and its association with E\u2010cadherin in adherens junction formation. Modulation of Dsg3 levels, either by Dsg3 silencing or over\u2010expression, alters Src activity and its association with E\u2010cadherin. Dsg3 silencing caused retardation of calcium\u2010induced E\u2010cadherin junction assembly and a reduction of desmosomal protein expression. Furthermore, we provide evidence that this signalling pathway is involved, at least in part, in the pathophysiology of pemphigus. Along with the reduced expression of Dsg3, loss and disruption of E\u2010cadherin and a concomitant decreased pSrc signalling was identified in the basal keratinocytes surrounding the blisters in PV. These findings suggest a novel function for Dsg3 in the control of E\u2010cadherin\u2013Src signalling and cell\u2013cell adhesion. Copyright \u00a9 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.3982","type":"journal-article","created":{"date-parts":[[2012,1,4]],"date-time":"2012-01-04T21:16:30Z","timestamp":1325711790000},"page":"81-93","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Non\u2010junctional human desmoglein 3 acts as an upstream regulator of Src in E\u2010cadherin adhesion, a pathway possibly involved in the pathogenesis of pemphigus vulgaris"],"prefix":"10.1002","volume":"227","author":[{"given":"Siu Man","family":"Tsang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Piper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edel A","family":"O'Toole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Grose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R","family":"Hart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Garrod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farida","family":"Fortune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,2,17]]},"reference":[{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.6.4053"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2006.00499_1.x"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90360-B"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12343081"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00463.x"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199907)29:07<2233::AID-IMMU2233>3.0.CO;2-4"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501365200"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602973103"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.141.6.1449"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200105140"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.4.823"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512447200"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611365200"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2009.10.005"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710046200"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1997.3890"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2008.08971.x"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00533.2006"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.98.6.1973"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1080\/08916930600971836"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01271"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/212439"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.07.014"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1080\/09687680210132476"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00366-6"},{"key":"e_1_2_8_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1356"},{"key":"e_1_2_8_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/35043032"},{"key":"e_1_2_8_29_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000125"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/jid.1967.86"},{"key":"e_1_2_8_31_2","first-page":"345","article-title":"Epidermal acantholysis induced in vitro by pemphigus autoantibody. 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