Cell death-induced activation of epidermal growth factor receptor in keratinocytes: Implications for restricting epidermal damage in dermatitis

Mihail S. Iordanov, Aaron J. Sundholm, Eric L. Simpson, Jon M. Hanifin, Olga P. Ryabinina, Remy J. Choi, Veselina B. Korcheva, Pascal Schneider, Bruce E. Magun

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21 Scopus citations

Abstract

Recent findings have implicated Fas/Fas ligand (FasL) in mediating the death of keratinocytes in spongiotic lesions. We asked whether dying keratinocytes could potentially initiate a protective response of the skin to limit the destruction of the epidermis in the spongiotic areas. In addition to apoptosis, treatment of keratinocyte cultures in vitro with FasL triggers a profound phoshorylation of the epidermal growth factor receptor (EGFR) and of its downstream effectors ERK and protein kinase B (PKB/Akt). Using a variety of inhibitors and blocking antibodies, we demonstrated that: (i) apoptosis is required for the generation of the signal(s) leading to the activation of EGFR, ERK, and Akt; (ii) the activation of EGFR, ERK, and Akt by FasL is indeed mediated by its bona fide receptor Fas; (iii) the activation of EGFR is essential for the subsequent activation of ERK and Akt; and (iv) apoptotic keratinocytes secrete soluble EGFR ligands (including amphiregulin) that are processed from membrane-bound proligand forms by metalloproteinase(s). Our findings demonstrate a potential mechanism for the restriction and repair of spongiotic damage in eczemas.

Original languageEnglish (US)
Pages (from-to)134-142
Number of pages9
JournalJournal of Investigative Dermatology
Volume125
Issue number1
DOIs
StatePublished - Jul 2005

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Keywords

  • Apoptosis
  • Dermatitis
  • Spongiosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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