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Published on: December 14, 2015
Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting
Mihail S Iordanov1, Aaron J Sundholm, Eric L Simpson
1Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, USA.
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.
Insights
Dying skin cells (keratinocytes) trigger a repair process in eczema by activating the epidermal growth factor receptor (EGFR) pathway, limiting epidermal damage.
Area of Science:
- Dermatology
- Cell Biology
- Immunology
Background:
- Fas/Fas ligand (FasL) signaling is implicated in keratinocyte death in spongiotic lesions.
- The role of dying keratinocytes in initiating protective skin responses remains unclear.
Purpose of the Study:
- To investigate if dying keratinocytes can initiate a protective response to limit epidermal destruction in spongiotic areas.
- To elucidate the molecular mechanisms underlying this protective response.
Main Methods:
- In vitro keratinocyte cultures treated with FasL.
- Analysis of epidermal growth factor receptor (EGFR) phosphorylation and downstream signaling (ERK, Akt).
- Use of inhibitors and blocking antibodies to dissect signaling pathways.
Main Results:
- FasL-induced apoptosis is necessary for EGFR, ERK, and Akt activation.
- EGFR activation is essential for subsequent ERK and Akt activation.
- Apoptotic keratinocytes release soluble EGFR ligands, mediated by metalloproteinases.
Conclusions:
- Dying keratinocytes activate EGFR signaling, suggesting a self-repair mechanism.
- This pathway may play a crucial role in limiting and repairing spongiotic damage in eczematous skin conditions.
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