Eph/ephrin signaling in epidermal differentiation and disease

Abstract

Eph receptor tyrosine kinases mediate cell-cell communication by interacting with ephrin ligands residing on adjacent cell surfaces. In doing so, these juxtamembrane signaling complexes provide important contextual information about the cellular microenvironment that helps orchestrate tissue morphogenesis and maintain homeostasis. Eph/ephrin signaling has been implicated in various aspects of mammalian skin physiology, with several members of this large family of receptor tyrosine kinases and their ligands present in the epidermis, hair follicles, sebaceous glands, and underlying dermis. This review focuses on the emerging role of Eph receptors and ephrins in epidermal keratinocytes where they can modulate proliferation, migration, differentiation, and death. The activation of Eph receptors by ephrins at sites of cell-cell contact also appears to play a key role in the maturation of intercellular junctional complexes as keratinocytes move out of the basal layer and differentiate in the suprabasal layers of this stratified, squamous epithelium. Furthermore, alterations in the epidermal Eph/ephrin axis have been associated with cutaneous malignancy, wound healing defects and inflammatory skin conditions. These collective observations suggest that the Eph/ephrin cell-cell communication pathway may be amenable to therapeutic intervention for the purpose of restoring epidermal tissue homeostasis and integrity in dermatological disorders.

Fig. 1

Eph receptors and ephrin ligands mediate cell–cell communication. Eph receptor tyrosine kinases interact with ephrin ligands residing on adjacent cell surfaces. Humans possess nine EphA (1–8/10) and five EphB (1–4/6) receptor sub-types, five ephrin-A (1–5) and three ephrin-B (1–3) ligands. Eph receptors are type I transmembrane spanning proteins that consist of a ligand binding domain (LBD), a cysteine-rich region (C), an epidermal growth factor (EGF)-like motif (E), fibronectin type-III repeats (F), a transmembrane domain (TMD), a juxtamembrane domain (JMD), a kinase domain (KD), a sterile-α-motif (SAM)-domain, and a PSD95/Dlg/ZO1 (PDZ)- protein binding site. Both subclasses of ephrin ligands consist of an N-terminal receptor binding domain (RBD). However, ephrin-A ligands are glycosylphosphatidylinositol (GPI)-linked whereas ephrin-B ligands are trans-membrane proteins and contain a cytoplasmic PDZ-tail. Upon engaging ephrins, bidirectional signaling is initiated where forward and reverse signaling take place in the receptor and ligand expressing cell, respectively.

Fig. 2

Eph receptors and ephrin ligands are compartmentalized in the epidermis. (A) The epidermis consists of four histologically distinct layers which are termed stratum: basale (SB), spinosum (SS), granulosum (SG), and corneum (SC). The epidermal layers are characterized by the expression of several markers of differentiation. Keratin intermediate filaments 5/14 (K5/14) and desmoglein 3 (Dsg3) are present in the basal layer while K1/10, desmoglein 1 (Dsg1), and desmocollin 1 (Dsc1) are concentrated in the more differentiated suprabasal layers of the epidermis. A summary of the distribution of EphA receptors and ephrin-A ligands is presented to the right of the schematic. (B) A 1 μm plastic section of human skin was stained with a trichrome solution (left panel). Black hyphens delineate all four layers of the human epidermis. Human skin samples were immunostained for A class receptors (EphA4) and ligands (ephrin-A1) (right two panels). (Scale bar: 50 μM) Ephrin-A ligands are restricted to the basal layer whereas EphA receptors are expressed throughout all layers of the epidermis.

Fig. 3

Eph receptors and ephrin ligands are functionally integrated with intercellular adhesion complexes. (A) A cartoon depiction of two polarized simple epithelial cells joined together by adherens junctions, desmosomes and tight junctions (TJ). Hemidesmosomes anchor these epithelial cells to the basement membrane. (B) Intercellular junctions undergo maturation in a differentiation-dependent manner that corresponds with the compartmentalized distribution of Eph receptors and ephrin ligands.