Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
Compound
Query: UNIPROT:P39060 (
endostatin
)
2,284
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The exact molecular mechanism of how
endostatin
inhibits angiogenesis and tumor growth remains uncharacterized. Here, we report that
endostatin
specifically binds to the cell surface nucleolin with high affinity. Blockage of nucleolin by a neutralizing antibody or knockdown of nucleolin by the RNA interference results in loss of antiendothelial activities of
endostatin
. Importantly, a neutralizing antinucleolin antibody abrogates the antiangiogenic and antitumor activities of
endostatin
in vivo.
Nucleolin
and
endostatin
are colocalized on the cell surface of endothelial cells of angiogenic blood vessels in the tumor environment. Finally, we found that
endostatin
is internalized and transported into cell nuclei of endothelial cell via nucleolin. In the nucleus, the phosphorylation of nucleolin, which is critical for cell proliferation, can be inhibited by
endostatin
. Our studies demonstrate that nucleolin is a novel functional receptor for
endostatin
, and mediates the antiangiogenic and antitumor activities of
endostatin
. These findings also provide mechanistic insights of how
endostatin
specifically inhibits proliferating endothelial cell growth and angiogenesis.
...
PMID:Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin. 1761 92
Endostatin is a potent angiogenesis inhibitor with heparin-dependent activities.
Nucleolin
, a novel functional receptor of
endostatin
, mediates both the internalization to endothelial cells and the antiangiogenic activity of
endostatin
. To define the exact role of the heparin binding motif in mediating the interaction between
endostatin
and its receptor nucleolin, up to six arginine residues (R155, R158, R184, R270, R193, and R194) located in the heparin binding motif of
endostatin
were substituted by alanine to make double, quadruple, or hexad point mutations, respectively. Contributions of the heparin binding motif to both the interaction with nucleolin and the biological activities of
endostatin
were investigated from in vitro to in vivo. Here we show that Arg to Ala point mutagenesis of the heparin binding motif does not interrupt the folding of
endostatin
but significantly impairs the interaction between
endostatin
and nucleolin. Double and quadruple mutants showed significantly decreased internalization to endothelial cells and antitumor activities, while the hexad Arg to Ala mutant completely lost its interaction with nucleolin and biological functions. Taken together, the present study demonstrates that the arginine clusters in the heparin binding motif of
endostatin
significantly contribute to its interaction with receptor nucleolin and mediate the antiangiogenic and antitumor activities of
endostatin
.
...
PMID:The heparin binding motif of endostatin mediates its interaction with receptor nucleolin. 1987 79
