Cell surface glypicans are low-affinity endostatin receptors

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Endostatin, a fragment of collagen XVIII, is recognized for its potent anti-angiogenic properties.
• Identifying the specific endothelial cell surface receptors for endostatin is crucial for understanding its mechanism of action.

Purpose of the Study:

• To identify the endothelial cell surface receptor(s) responsible for endostatin binding.
• To elucidate the role of identified receptors in mediating endostatin's biological activities, including its function in renal tubular cell morphogenesis.

Main Methods:

• Utilized alkaline phosphatase-tagged endostatin to study binding affinities to endothelial cells.
• Employed expression cloning to identify receptor candidates.
• Conducted biochemical and genetic studies to confirm the role of heparan sulfate glycosaminoglycans in glypican-endostatin interaction.
• Performed antisense experiments to assess the functional significance of glypicans.

Main Results:

• Endostatin exhibited two binding affinities to endothelial cells.
• Glypican, a cell surface proteoglycan, was identified as the lower-affinity receptor for endostatin.
• The heparan sulfate glycosaminoglycans of glypicans were found to be critical for endostatin binding.
• Endostatin specifically selected an octasulfated hexasaccharide from heparin.
• Glypicans were also identified as low-affinity receptors for endostatin in renal tubular cells, mediating its role in branching morphogenesis.

Conclusions:

• Glypicans function as low-affinity receptors for endostatin on endothelial cells and renal tubular cells.
• The heparan sulfate chains of glypicans are essential for mediating endostatin binding and its anti-angiogenic and morphogenetic activities.
• Antisense studies underscore the critical role of glypicans in mediating endostatin's biological effects.