CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and...

Area of Science:

• Cell Biology
• Vascular Biology
• Biochemistry

Background:

• Cell-surface retention sequence (CRS) binding protein-1 (CRSBP-1), identical to LYVE-1, binds PDGF-BB and VEGF-A via CRS motifs.
• CRSBP-1 exhibits dual ligand binding, interacting with CRS-containing proteins and hyaluronic acid, highlighting its role in lymphatic function.

Purpose of the Study:

• To elucidate the mechanism by which CRSBP-1 ligands affect lymphatic endothelial cell (LEC) intercellular junctions.
• To investigate the signaling pathway involved in ligand-induced opening of lymphatic vessels.

Main Methods:

• Immunofluorescence microscopy and Transwell permeability assays to assess intercellular adhesion and permeability in LEC monolayers.
• Analysis of the CRSBP-1-PDGFβR-β-catenin complex and VE-cadherin phosphorylation.
• In vivo studies in wild-type and Crsbp1-null mice using FITC-dextran and edema fluid to evaluate lymphatic vessel permeability.

Main Results:

• CRSBP-1 ligands disrupt VE-cadherin-mediated intercellular adhesion and open LEC monolayers.
• Ligand binding triggers tyrosine phosphorylation within the CRSBP-1-PDGFβR-β-catenin complex, leading to VE-cadherin internalization.
• PDGFβR kinase inhibition prevents ligand-induced junction opening in vitro and in vivo, and this effect is absent in Crsbp1-null mice.

Conclusions:

• CRSBP-1 ligands open lymphatic intercellular junctions through a novel mechanism involving PDGFβR signaling and VE-cadherin regulation.
• This pathway is crucial for regulating lymphatic vessel permeability and fluid transport.
• Targeting PDGFβR kinase may offer therapeutic strategies for modulating lymphatic function.