title: A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis.
abstract: The pemphigus family of autoimmune bullous disorders is characterized by autoantibody binding to desmoglein 1 and/or 3 (dsg1/dsg3). In this study we show that EGF receptor (EGFR) is activated following pemphigus vulgaris (PV) IgG treatment of primary human keratinocytes and that EGFR activation is downstream of p38 mitogen-activated protein kinase (p38). Inhibition of EGFR blocked PV IgG-triggered dsg3 endocytosis, keratin intermediate filament retraction, and loss of cell-cell adhesion in vitro. Significantly, inhibiting EGFR prevented PV IgG-induced blister formation in the passive transfer mouse model of pemphigus. These data demonstrate cross-talk between dsg3 and EGFR, that this cross-talk is regulated by p38, and that EGFR is a potential therapeutic target for pemphigus. Small-molecule inhibitors and monoclonal antibodies directed against EGFR are currently used to treat several types of solid tumors. This study provides the experimental rationale for investigating the use of EGFR inhibitors in pemphigus.
authors: Department of Dermatology, University of North Carolina, Chapel Hill, NC 27599-7287, USA.
authors: Meryem
authors: M
authors: Bektas
authors: Puneet S
authors: PS
authors: Jolly
authors: Paula
authors: P
authors: Berkowitz
authors: Masayuki
authors: M
authors: Amagai
authors: David S
authors: DS
authors: Rubenstein
mesh_terms: D000051:Acantholysis / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion; D002478:Cells, Cultured; D051182:Desmogleins / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D010392:Pemphigus / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051182:Desmogleins; D003902:Detergents; D007074:Immunoglobulin G; D034741:RNA, Small Interfering; D007633:Keratins; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases
references: Am J Pathol. 2008 Dec;173(6):1628-36
references: 18988808
references: Exp Dermatol. 2009 Sep;18(9):771-80
references: 19552768
references: J Clin Invest. 1988 Mar;81(3):807-12
references: 3343340
references: J Immunol. 2003 Feb 15;170(4):2170-8
references: 12574390
references: J Biol Chem. 1998 Oct 16;273(42):27111-7
references: 9765228
references: J Biol Chem. 2004 Aug 27;279(35):37191-200
references: 15205458
references: J Cell Biol. 1994 Dec;127(5):1375-80
references: 7962096
references: EMBO J. 2006 Sep 20;25(18):4195-206
references: 16932740
references: Mol Cell Biol. 2003 Oct;23(20):7391-402
references: 14517306
references: Mol Biol Cell. 2009 Jan;20(1):328-37
references: 18987342
references: Mol Cell Biol. 2009 Oct;29(20):5529-39
references: 19687304
references: J Invest Dermatol. 1999 Jan;112(1):67-71
references: 9886266
references: J Invest Dermatol. 2004 Sep;123(3):564-73
references: 15304097
references: Cancer Res. 2007 Jan 15;67(2):727-34
references: 17234784
references: J Immunol. 1986 Feb 15;136(4):1227-30
references: 3511144
references: Am J Pathol. 2008 Jul;173(1):14-24
references: 18556782
references: J Cell Physiol. 2007 Feb;210(2):411-6
references: 17058228
references: Curr Opin Cell Biol. 1999 Apr;11(2):184-9
references: 10209149
references: Nat Rev Mol Cell Biol. 2002 Aug;3(8):600-14
references: 12154371
references: EMBO J. 2006 Jul 26;25(14):3298-309
references: 16871158
references: Traffic. 2006 Jun;7(6):686-98
references: 16683917
references: J Biol Chem. 2001 Jul 6;276(27):24871-80
references: 11335725
references: Arch Dermatol Res. 1999 Nov;291(11):606-13
references: 10638334
references: J Biol Chem. 2010 Mar 19;285(12):8936-41
references: 20093368
references: Am J Pathol. 2009 Feb;174(2):475-85
references: 19147829
references: EMBO J. 1997 Aug 1;16(15):4597-605
references: 9303304
references: J Biol Chem. 2005 Dec 2;280(48):40355-63
references: 16183992
references: J Cell Biol. 2009 Jun 29;185(7):1243-58
references: 19546243
references: EMBO J. 1998 May 1;17(9):2574-83
references: 9564040
references: J Biol Chem. 2008 Jun 27;283(26):18303-13
references: 18434319
references: J Biol Chem. 2009 May 1;284(18):12524-32
references: 19270308
references: J Cell Biol. 2006 Dec 4;175(5):721-7
references: 17130286
references: Am J Physiol Cell Physiol. 2009 Jan;296(1):C162-72
references: 18987254
references: Cancer Lett. 2009 May 8;277(1):108-13
references: 19138820
references: J Biol Chem. 2005 Jun 24;280(25):23778-84
references: 15840580
references: J Exp Med. 1984 Nov 1;160(5):1509-18
references: 6491602
references: Biochem J. 2010 Aug 1;429(3):403-17
references: 20626350
references: Autoimmunity. 2006 Nov;39(7):587-90
references: 17101502
references: J Biol Chem. 2007 May 4;282(18):13804-12
references: 17344213
references: Cell. 1991 Nov 29;67(5):869-77
references: 1720352
references: J Biol Chem. 2006 Mar 17;281(11):7623-34
references: 16377623
references: Oncogene. 2010 May 27;29(21):3146-52
references: 20208558
references: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12855-60
references: 16908851
references: Autoimmunity. 2006 Nov;39(7):563-75
references: 17101500