Cell surface glypicans are low-affinity endostatin receptors.
Endostatin, a collagen XVIII fragment, is a potent anti-angiogenic protein. We sought to identify its endothelial cell surface receptor(s). Alkaline phosphatase- tagged endostatin bound endothelial cells revealing two binding affinities. Expression cloning identified glypican, a cell surface proteoglycan as the lower-affinity receptor. Biochemical and genetic studies indicated that glypicans' heparan sulfate glycosaminoglycans were critical for endostatin binding. Furthermore, endostatin selected a specific octasulfated hexasaccharide from a sequence in heparin. We have also demonstrated a role for endostatin in renal tubular cell branching morphogenesis and show that glypicans serve as low-affinity receptors for endostatin in these cells, as in endothelial cells. Finally, antisense experiments suggest the critical importance of glypicans in mediating endostatin activities.
Karumanchi
S A
SA
Department of Medicine and the Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
Jha
V
V
Ramchandran
R
R
Karihaloo
A
A
Tsiokas
L
L
Chan
B
B
Dhanabal
M
M
Hanai
J I
JI
Venkataraman
G
G
Shriver
Z
Z
Keiser
N
N
Kalluri
R
R
Zeng
H
H
Mukhopadhyay
D
D
Chen
R L
RL
Lander
A D
AD
Hagihara
K
K
Yamaguchi
Y
Y
Sasisekharan
R
R
Cantley
L
L
Sukhatme
V P
VP
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism*; D043170:Collagen Type XVIII; D006224:Cricetinae; D043169:Endostatins; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009844:Oligosaccharides / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D013431:Sulfates / Q000378:metabolism / Q000494:pharmacology
D043170:Collagen Type XVIII; D043169:Endostatins; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D009844:Oligosaccharides; D010446:Peptide Fragments; D013431:Sulfates; D006493:Heparin; D003094:Collagen