14-3-3 is a highly conserved, ubiquitously expressed protein family, and consists of seven mammalian isoforms (α, β, σ, δ, ε, η, γ, τ, ζ). Since their initial discovery in 1967, the 14-3-3 proteins have gained special importance as regulators in crucial biological processes such as cell cycle control, signal transduction, apoptosis, neuronal development and malignant transformation. Emerging evidence has shown that 14-3-3 sigma, also called stratifin, is unique among the isoforms due to its preference for homodimerization and specific selectivity for target binding proteins,  and because it is most abundantly expressed in epithelial cells. Upon binding to the aminopeptidase N/CD13 receptor, stratifin stimulates the expression of matrix metalloproteinases (MMPs) and modulates extracellular matrix turnover which is a key determinant for successful wound healing. The identification of aminopeptidase N (APN) as a candidate receptor for the stratifin-mediated MMP-1 up-regulation in fibroblasts extends the functionality of the stratifin protein to cell migration and adhesion, immune response, differentiation, and metastasis. Further characterization of the stratifin/ APN-mediated signalling will provide valuable information needed for deciphering the intricacy of tissue regeneration and wound repair. In this review, the recent finding on the role of stratifin as a signalling factor in epidermal-dermal crosstalk and its receptor will be outlined and discussed.