Deleted in Colorectal Carcinoma (DCC) Binds Heparin via Its Fifth Fibronectin Type III Domain

DCC (deleted incolorectal carcinoma) is a broadly expressed cell-surface receptor. Netrin-1 was recently identified as a DCC ligand in brain, but the possibility of other DCC ligands was suggested by the finding that an anti-DCC antibody (clone AF5) neutralized netrin-1-dependent commissural axon ou...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-10, Vol.272 (43), p.26940-26946
Main Authors: Bennett, Kelly L., Bradshaw, Jeff, Youngman, Trent, Rodgers, Julie, Greenfield, Brad, Aruffo, Alejandro, Linsley, Peter S.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Binding Sites
Cell Adhesion Molecules - chemistry
Cell Adhesion Molecules - metabolism
Cell Line
Cell Membrane - metabolism
Colorectal Neoplasms
DCC Receptor
Fibronectins - chemistry
Genes, Tumor Suppressor
Heparin - chemistry
Heparin - metabolism
Humans
Molecular Sequence Data
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Polymerase Chain Reaction
Protein Structure, Secondary
Receptors, Cell Surface
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Tumor Suppressor Proteins
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Summary:DCC (deleted incolorectal carcinoma) is a broadly expressed cell-surface receptor. Netrin-1 was recently identified as a DCC ligand in brain, but the possibility of other DCC ligands was suggested by the finding that an anti-DCC antibody (clone AF5) neutralized netrin-1-dependent commissural axon outgrowth without blocking DCC/netrin-1 interactions. Here we have searched for alternative cell-surface DCC ligands. A DCC-Ig fusion protein bound to neural and epithelial derived cell lines, indicating that these lines express ligand(s) for DCC. The cell-surface binding activity was mediated by the loop between ॆ-strands F and G of the fifth fibronectin type III repeat FNIII-D5. The loop included the sequence KNRR, which resembles heparin-binding motifs in other proteins. Heparinase and heparitinase treatment of cells reduced binding of DCC-Ig, suggesting that heparan sulfate proteoglycans are cell-surface DCC ligand(s). This was further supported by heparin blocking experiments and by binding of DCC-Ig to immobilized heparan sulfate. The interaction between DCC-Ig and heparan sulfate/heparin, both on the surface of cells and immobilized on plastic, was blocked by the same anti-DCC antibody that blocks netrin-1-dependent commissural axon outgrowth. Taken together, these findings suggest that the DCC-Ig/heparin interaction may contribute to the biological activity of DCC.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.43.26940