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J. Biol. Chem., Vol. 282, Issue 18, 13804-13812, May 4, 2007

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Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

CHARACTERIZATION OF NOVEL SIGNALING PATHWAYS DOWNSTREAM OF PEMPHIGUS VULGARIS ANTIGENS^*

Alex I. Chernyavsky, Juan Arredondo, Yasuo Kitajima, Miki Sato-Nagai, and Sergei A. Grando¹

From the Department of Dermatology, University of California, Davis, California 95816 and the Gifu University School of Medicine, Gifu 501-1194, Japan

Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by 45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by 50% and TUNEL positivity by 25%. The p38 MAPK inhibitor PD169316 inhibited these effects by 15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked 50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.

Received for publication, December 12, 2006 , and in revised form, January 29, 2007.

^* This work was supported in part by the International Pemphigus Research Fund (to S. A. G.). This work was presented in part at the Satellite Symposium of the 36th Annual Meeting of the European Society of Dermatological Research "Advances in Pemphigus and Pemphigoid," Paris, September 6-7, 2006, and published in the Abstract: Chernyavsky, A. I., and Grando, S. A. (2006) Characterization of Novel Signaling Pathways Downstream of Non-desmoglein Targets of Pathogenic Autoantibodies in Pemphigus Vulgaris, J. Investig. Dermatol. Vol. 126, p. 2352. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Dermatology, University of California Davis Medical Center, 3301 C St., Suite 1400, Sacramento, CA 95816. Tel.: 916-734-6057; Fax: 916-442-5702; E-mail: sagrando{at}ucdavis.edu.

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