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Laminin 5 Chain Metastasis- and Angiogenesis-Inhibiting Peptide Blocks Fibroblast Growth Factor 2 Activity by Binding to the Heparan Sulfate Chains of CD44

¹ Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland; ² Fourth Department of Internal Medicine, Nippon Medical School; ³ Respiratory Division of Internal Medicine, Tokyo Metropolitan Komagome Hospital; ⁴ Laboratory of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan; and ⁵ Graduate School of Environmental Earth Science, Hokkaido University, Sapporo, Japan

Requests for reprints: Hynda K. Kleinman, Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, NIH, Building 30, Room 433, 30 Convent Drive, MSC 4370 Bethesda, MD 20892-4370. Phone: 301-496-4069; Fax: 301-402-0897; E-mail: hkleinman{at}dir.nidcr.nih.gov.

Recently, we reported that the laminin 5 synthetic peptide A5G27 (RLVSYNGIIFFLK, residues 2,892-2,904) binds to the CD44 receptor of B16-F10 melanoma cells via the glycosaminoglycans on CD44 and inhibits tumor cell migration, invasion, and angiogenesis in a dominant-negative manner. Here, we have identified the potential mechanism of A5G27 activity using WiDr human colorectal carcinoma cells. WiDr cells bound to the laminin A5G27 peptide via the heparin-like and chondroitin sulfate B glycosaminoglycan side chains of CD44. Cell binding to fibroblast growth factor (FGF2) was blocked by laminin peptide A5G27 but not by either a scrambled version of this peptide or by another laminin peptide known to bind cell surface proteoglycans. FGF2 signaling involving tyrosine phosphorylation was also blocked by laminin peptide A5G27 but was not affected by peptide controls. Finally, we have shown that peptide A5G27 directly blocks FGF2 binding to heparin. Peptide A5G27 has sequence homology to a region on FGF2 that binds heparin and the FGF receptor and is important in FGF2 central cavity formation. We conclude that peptide A5G27 inhibits metastasis and angiogenesis by blocking FGF2 binding to the heparan sulfate side chains of CD44 variant 3, thus decreasing FGF2 bioactivity.

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