Novel insights into cadherin processing by subtilisin-like convertases.
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 alpha 1-anti-trypsin Portland (alpha 1-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.
Posthaus
Horst
H
Institute of Animal Pathology, University of Bern, Laenggass Str. 122, 3012 Bern, Switzerland.
Dubois
Claire M
CM
Müller
Eliane
E
D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D051183:Desmoglein 1; D051184:Desmoglein 3; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045683:Furin; D007313:Insecta / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013381:Subtilisins / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D015820:Cadherins; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; D004791:Enzyme Inhibitors; D011498:Protein Precursors; D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D043484:Proprotein Convertases; D013381:Subtilisins; D045683:Furin