Novel insights into cadherin processing by subtilisin-like convertases.

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Proprotein convertases (PCs) are enzymes involved in activating molecules and are implicated in tumor progression.
• The role of PCs in processing cadherin adhesion molecules, which act as tumor suppressors, is not well understood.
• Cadherins are vital for intercellular adhesion, and their loss is linked to tumor malignancy.

Purpose of the Study:

• To investigate the role of proprotein convertases (PCs) in the processing of desmosomal cadherins (Dsg1 and Dsg3).
• To determine the effect of PC inhibition on cadherin expression and processing in differentiating keratinocytes.

Main Methods:

• Utilized a baculovirus overexpression system to study PC substrates.
• Employed alpha 1-anti-trypsin Portland (alpha 1-PDX) to inhibit PCs in mouse keratinocytes.
• Analyzed protein and mRNA levels of E-cadherin, Dsg1, and Dsg3.

Main Results:

• Demonstrated that desmosomal cadherins Dsg1 and Dsg3 are substrates for the PC furin.
• PC inhibition in differentiating keratinocytes interfered with pro-epithelial (proE)-cadherin processing.
• Observed a significant reduction in E-cadherin, Dsg1, and Dsg3 protein levels, as well as Dsg1 mRNA.

Conclusions:

• Proprotein convertases (PCs) are involved in the processing of key cadherin adhesion molecules.
• PC inhibition has a broader negative impact on cadherin expression than previously thought.
• These findings suggest complex implications for the therapeutic use of PC inhibitors in cancer treatment due to their effect on cell adhesion.