EGFR regulation of epidermal barrier function

Abstract

Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammalian survival. This process is controlled, in part, by signal transduction and gene expression mechanisms, and the epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Using microarray analysis of a confluent cell density-induced model of keratinocyte differentiation, we identified 2,676 genes that are regulated by epidermal growth factor (EGF), a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all of the known essential processes of keratinocyte differentiation by 1) decreasing the expression of lipid matrix biosynthetic enzymes, 2) regulating numerous genes forming the cornified envelope, and 3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, EGF acted to impair epidermal barrier integrity, as shown by increased transepidermal water loss. As defective epidermal differentiation and disruption of barrier function are primary features of many human skin diseases, we used bioinformatic analyses to identify genes that are known to be associated with skin diseases. Compared with non-EGF-regulated genes, EGF-regulated genes were significantly enriched for skin disease genes. These results provide a systems-level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation, providing new insight into the role of EGFR imbalance in skin pathogenesis.

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

“…EGFR, especially when phosphorylated EGFR, is known to regulate the expression of numerous genes involved in differentiation (Tran et al, 2012). The abundance of EGFR and phosphorylated EGFR was assessed on western blots before and after confluence of keratinocyte cultures.…”

Combined treatment with sodium butyrate and PD153035 enhances keratinocyte differentiation

“…For RNA qRT-PCR, immunoblotting, and percentage cornified envelope (CE) formation, NHEKs were grown as previously described (8) and treated with SB (Calbiochem, San Diego, CA; 2 mM, unless otherwise indicated), PD153035 (Calbiochem, San Diego, CA; 300 nM), or EGF (Invitrogen, Carlsbad CA; 10 ng/ml), with each endpoint measured as previously described (2, 8). Levels of poly ADP-ribose polymerase (PARP) and cleaved PARP were detected by immunoblot using an anti-PARP antibody (Epitomics, Burlingame, CA).…”

“…In addition to its action to enhance keratinocyte migration and proliferation, it has been shown to impede all major processes of differentiation, namely cornified envelope, lipid biosynthesis, and tight junction formation (2, 3). Levels of this receptor and its ligands are elevated in the suprabasal layers of the epidermis in inflammatory hyperproliferative skin diseases (4).…”

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

“…Skin homeostasis is thought to be controlled by a balance of various factors present in the skin tissue that allows for flexibility in dealing with a changing environment (2). For example, epidermal growth factor family members and their receptors are known to control the differentiation and development of epidermal cells to maintain a normal epidermal component (3,4); proinflammatory cytokines such as IL-6 and IL-1β play important roles in wound healing and regeneration of epidermal tissue (5,6); and several cytokines are important for keratinocyte proliferation and differentiation in inflammatory disease conditions such as psoriasis (7,8). However, the precise signal transduction molecules activated by these cytokines and their receptors in skin barrier maintenance are not fully understood.…”