Fig. 8.

Model for Ctip2 functions in the proliferation and differentiation of epidermal keratinocytes. In proliferative keratinocytes, Ctip2 interacts with the EGFR promoter and positively regulates EGFR expression, thereby promoting keratinocyte proliferation and survival. Activated EGFR signaling also promotes Ctip2 phosphorylation and inhibits Ctip2 expression at the mRNA level (proliferating conditions). Keratinocytes entering spinous layers after exiting the basal layer express both Ctip2 and Notch1. Upon depletion of growth factors from cultured keratinocytes, equivalent to the exit of cells from the basal compartment, Ctip2 is recruited to the Notch1 promoter, positively regulating the expression of Notch1 and triggering onset of early differentiation. Subsequently elevated extracellular calcium levels facilitates onset of late differentiation and Ctip2 is degraded by high-calcium signaling through the SUMO–Ub–proteasomal pathway.