EGFR and cancer: In addition to a role for desmosomal scaffolding of the CSN in regulating normal epidermal differentiation and homeostasis, our data from a 3D organotypic cancer model suggests that EGFR neddylation may contribute to elevated EGFR/MAPK signaling in human diseases including inherited keratodermas (Harmon et al., 2013) and cancers such as head and neck squamous cell carcinoma (HNSCC) (Figure 6a–c).