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Journal of Pharmacology and Experimental Therapeutics

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OtherCHEMOTHERAPY/GENE THERAPY

Biochemical Characterization of the Binding of Echistatin to Integrin αvβ3 Receptor

C. Chandra Kumar, Huiming-Nie, Christine Prorock Rogers, Mike Malkowski, Eugene Maxwell, Joseph J. Catino and Lydia Armstrong
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 843-853;
C. Chandra Kumar
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Huiming-Nie, Christine Prorock Rogers
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Mike Malkowski
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Eugene Maxwell
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Joseph J. Catino
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Lydia Armstrong
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Abstract

Echistatin is a 49-amino-acid peptide belonging to the family of disintegrins that are derived from snake venoms and are potent inhibitors of platelet aggregation and cell adhesion. Integrin αvβ3 receptor plays a critical role in several physiological processes such as tumor-induced angiogenesis, tumor cell metastasis, osteoporosis and wound repair. In this study, we have characterized the binding of echistatin to purified integrin αvβ3 receptor and the form expressed on human embryonic kidney 293 cells. We show that both purified and membrane-bound integrin αvβ3 binds to echistatin with a high affinity, which can be competed efficiently by linear and cyclic peptides containing the RGD sequence. Previous studies have shown that αvβ3 binds to vitronectin in a nondissociable manner, whereas an RGD-containing peptide derived from vitronectin binds in a dissociable manner with aKd of 9.4 × 10−7 M. Our studies indicate that radiolabeled echistatin binds to αvβ3 in a nondissociable manner, similar to native echistatin. However, echistatin does not support the adhesion of 293 cells expressing αvβ3 receptor because of poor binding to plastic dishes and is a potent antagonist of the adhesion of these cells to vitronectin. These studies demonstrate that echistatin binding to αvβ3 is of high affinity and irreversible similar to vitronectin and provides an alternate ligand for high-throughput screening for αvβ3 antagonists.

Footnotes

  • Send reprint requests to: Dr. C. Chandra Kumar, Dept. of Tumor Biology, Schering Research Institute, 2015, Galloping Hill Road, Kenilworth, NJ 07033.

  • Abbreviations:
    DMEM
    Dulbecco’s modified Eagle’s medium
    PMSF
    phenylmethylsulfonyl fluoride
    SDS
    sodium dodecyl sulfate
    PBS
    phosphate-buffered saline
    FACS
    fluorescence-activated cell sorter
    VN
    vitronectin
    PAGE
    polyacrylamide gel electrophoresis
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    • Received February 13, 1997.
    • Accepted July 16, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherCHEMOTHERAPY/GENE THERAPY

Biochemical Characterization of the Binding of Echistatin to Integrin αvβ3 Receptor

C. Chandra Kumar, Huiming-Nie, Christine Prorock Rogers, Mike Malkowski, Eugene Maxwell, Joseph J. Catino and Lydia Armstrong
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 843-853;

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OtherCHEMOTHERAPY/GENE THERAPY

Biochemical Characterization of the Binding of Echistatin to Integrin αvβ3 Receptor

C. Chandra Kumar, Huiming-Nie, Christine Prorock Rogers, Mike Malkowski, Eugene Maxwell, Joseph J. Catino and Lydia Armstrong
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 843-853;
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