Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis.
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.
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, USA.
Mihail S
MS
Iordanov
Aaron J
AJ
Sundholm
Eric L
EL
Simpson
Jon M
JM
Hanifin
Olga P
OP
Ryabinina
Remy J
RJ
Choi
Veselina B
VB
Korcheva
Pascal
P
Schneider
Bruce E
BE
Magun
D017209:Apoptosis; D018929:Cell Culture Techniques; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D066246:ErbB Receptors / Q000378:metabolism*; D053222:Fas Ligand Protein; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D015398:Signal Transduction
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D066246:ErbB Receptors