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). Here, EGFR is linked to head and neck squamous cell carcinoma.