Dysregulations within the epidermal proteolytic network can cause hyperproliferative and inflammatory disorders. Although the metalloprotease meprin α is localized in the stratum basale in healthy skin, increased levels are found in the upper epidermal layers in wound healing and psoriatic lesions. To investigate a link between meprin α expression and keratinocyte proliferation, we developed a mouse model for inducible expression of pathological meprin α levels (ie, K5Mα mice). K5Mα mice developed a skin phenotype characterized by hyperkeratosis, acanthosis, parakeratosis, and barrier defect. Keratinocyte hyperproliferation and local inflammation were induced upon induction of meprin α expression. By N-terminomics, we identified dermokine, a regulator of keratinocyte proliferation and epidermal immune response, as a putative substrate of meprin α. We validated the proteolysis and identified the cleavage site, which is highly conserved in mammals, suggesting that dermokine degradation by meprin α represents a central mechanism in wound healing and hyperproliferative skin diseases.