849 Enhancement of cutaneous wound healing by Dsg2-augmented uPAR secretion

Desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. While lowly expressed in the basal epidermis, overexpression is a common feature of both experimental and clinical samples of melanoma and non-melanoma malignancies. However, the role of Dsg2 in the normal skin and during cancer progression is poorly understood. Here, we show that transgenic mice overexpressing Dsg2 in basal keratinocytes (K14-Dsg2) primed the activation of mitogenic pathways, but did not induce dramatic epidermal changes or alter susceptibility to DMBA/TPA-induced tumor development. Interestingly, we observed accelerated full-thickness wound closure and enhanced keratinocyte proliferation in the wounds. Analysis using proteome profiler antibody array revealed that in cultured keratinocytes, Dsg2 augmented the release of several chemokines and receptors, including IL-6R, TNF-αR and uPAR. Ablation of uPAR in knockout mice has been shown to impair cutaneous wound healing. Here, we observed increased expression and proteolytic processing of uPAR in the skin of the K14-Dsg2 mice. Further analysis illustrated sustained, enhanced uPAR expression in keratinocytes of wounded skin and increased soluble uPAR levels in the dermis. Full-length uPAR was also exported in exosomes secreted by keratinocytes, suggesting that exosomes could also facilitate intercellular transfer of the receptor. This study demonstrates that Dsg2 promotes wound healing through the upregulation of uPAR, activating a signaling cascade involved in inflammation and wound repair; and implicates exosomes as a mediator of this process.