Proteolytic processing regulates receptor specificity and activity of VEGF-C

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Vascular Endothelial Growth Factor C (VEGF-C) is a recently identified member of the platelet-derived growth factor (PDGF)/VEGF family.
• VEGF-C acts as a ligand for endothelial receptor tyrosine kinases VEGFR-3 and VEGFR-2.
• The VEGF homology domain constitutes only a portion of the VEGF-C precursor.

Purpose of the Study:

• To investigate the role of post-translational processing in VEGF-C secretion and function.
• To elucidate the structural characteristics of mature VEGF-C.
• To understand the structure-function relationships within the PDGF/VEGF family.

Main Methods:

• Analysis of VEGF-C processing and activity.
• Recombinant expression of mature VEGF-C in yeast.
• Binding and activation assays for VEGFR-3 and VEGFR-2.
• Assessment of VEGF-C's effects on vascular permeability, endothelial cell migration, and proliferation.

Main Results:

• Stepwise proteolytic processing generated VEGF-C forms with enhanced VEGFR-3 activity.
• Only fully processed VEGF-C activated VEGFR-2.
• Recombinant mature VEGF-C bound and activated both VEGFR-3 and VEGFR-2.
• Mature VEGF-C increased vascular permeability and promoted endothelial cell migration and proliferation.
• Mature VEGF-C predominantly formed non-covalent homodimers, unlike other PDGF/VEGF family members.

Conclusions:

• Proteolytic processing acts as a critical regulator of VEGF-C activity.
• Novel structure-function relationships were identified for VEGF-C within the PDGF/VEGF family.
• The findings provide insights into the mechanisms controlling VEGF-C signaling and its biological effects.