Our data show that Tyr51 in the extracellular domain of syndecan-2 (residues 41 to 60) mediates the interaction of syndecan-2 with the α2 helix-loop-α3 helix in the pro-domain of MMP-7, and that this interaction is critical for the localization of pro-MMP-7 on the cell surface, its processing into active MMP-7, and the syndecan-2-mediated regulation of tumorigenic activity of colon cancer cells. Here, MMP7 is linked to malignant colon neoplasm.