Proprotein convertases (PCs) are known to activate many important molecules and their overexpression plays a significant role in tumor progression. Only little is known about the involvement of PCs in the processing of cadherin adhesion molecules, which are potent tumor suppressors. Here we show in a baculovirus overexpression system that the desmosomal cadherins Dsg1 and Dsg3 are substrates for the PC furin. Accordingly, inhibition of PCs in differentiating mouse keratinocytes by α1‐anti‐trypsin Portland (α1‐PDX) negatively interfered with pro‐epithelial (proE)‐cadherin processing, but unexpectedly also resulted in a dramatic reduction of E‐cadherin, Dsg1 and Dsg3 protein and Dsg1 mRNA. Because loss of intercellular adhesion is a rate‐limiting step in the transition from benign to malignant tumors, these results have significant implications for the use of PC inhibitors as possible therapeutic tools.