Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology

Abstract

The epidermal growth factor receptor (EGFR) network, including its seven ligands and four related receptors, represents one of the most complex signaling systems in biology. In many tissues, including the skin and its appendages (notoriously the hair follicles), its correct function is necessary for proper development and tissue homeostasis, and its deregulation rapidly results in defects in cellular proliferation and differentiation. The consequences are impaired wound healing, development of psoriasis-like lesions, structural and functional defects of the hair follicles, and tumorigenesis. In addition to in vitro experiments and data from clinical studies, several genetically modified mouse models displaying alterations in the interfollicular skin and hair follicles attributable to mutations in components of the EGFR system have been reported. These animals, in many cases representing bona fide models of known human diseases, have been seminal in the study of the role of EGFR and its ligands in the skin and its appendages. In this review, we take the multiple phenotypes of these animal models as a basis to summarize and discuss the effects elicited by members of the EGFR system in diverse aspects of skin biology and pathology, including cellular proliferation and differentiation, wound healing, hair follicle morphogenesis, and tumorigenesis.

Figure 1

Photographs published by Clyde E. Keeler in 1935 comparing a wa-1 (A), a wa-2 (C), and a normal coated mouse (B). Reproduced from The Journal of Heredity, 1935, Vol 26, pp 189–191, with permission from Oxford University Press.

Figure 2

The EGFR network can be viewed as a multilayered system. The input layer comprises the seven EGFR ligands. In the signal processing layer, the four receptors form 10 possible dimeric combinations after ligand binding. Note that ERBB2 and ERBB3 homodimers are nonfunctional because of a lack of a ligand or to a dead kinase, respectively. Once activated by a ligand (1), molecules with adaptor or enzymatic function are recruited to the receptors and activate downstream signaling pathways including the RAS-MAPK cascade (2), which is shown in more detail because of its relevance for keratinocyte proliferation and survival. Finally, activated downstream components change the activity of multiple nuclear transcription factors, altering the cellular transcriptional program (3). Signaling via the STAT, PLC-PKC, and PI3K-AKT pathways are also important in mediating EGFR activity (4). EGFR signaling is also activated by EGFR-independent signaling pathways (nonclassical use) including ligand-free receptor activation. The output layer is the result of the altered cellular transcriptional program and represents the cellular effects elicited by the combined activity of the previous layers.