FIGURE 2.

Epidermal growth factor receptor (EGFR) signaling as a critical regulator of desmosomes (created with biorender.com). (Upper panel) Modification of desmosomes by EGFR signaling. Binding of EGF family growth factors to their receptors activates the canonical RAS/RAF/MAPK signaling pathway. Several kinases of the pathway can phosphorylate desmosomal cadherins and PKPs, thereby affecting their stability as well as their localization at the cell membrane. At the same time, EGFR signaling alleviates transcription of desmosomal genes and promotes cell cycle gene expression thereby controlling the balance between proliferation, differentiation and cell-cell adhesion. (Lower panel) Impact of desmosomal proteins on EGFR signaling. The desmosomal cadherins DSG1-3 and DSC2 as well as PKP2 co-localize or interact with the EGFR at the cell membrane, thereby either activating or inhibiting RAS/RAF/MAPK signaling. DSC1/3 and PKP3 affect RAS/RAF/MAPK signaling probably without interfering directly with the EGFR.