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Gelatinase A (matrix metalloproteinase-2, MMP-2) binds to several proteins through its collagen-binding domains (CBDs). Surface plasmon resonance analysis revealed a strong interaction between CBD123 and thrombospondin-1 (TSP-1), with a K D value of 2 × 10 − 9 M. CBD123, as well as individual domains, behave as competitive inhibitors of the TSP-1-directed endocytic clearance of active MMP-2, but not of its latent form, by HT1080 fibrosarcoma cells. Enhanced level of active MMP-2 in conditioned medium was associated to increased matrigel invasion. Similarly, GGWSHWSPWSS and GGWSHW peptides, as tryptophan-rich peptides within properdin-repeat motifs (TSRs) of TSP-1, promoted MMP-2 accumulation and cell invasiveness. Our data document the importance of TSP-1 in promoting MMP-2-mediated cancer cell invasion through interaction between CBDs of the enzyme and TSRs motifs of TSP-1.

Human apolipoprotein(a), a risk factor for heart disease, has over 80% sequence identity to plasminogen. Plasminogen contains five distinct kringle domains plus a catalytic protease subunit. Human apo(a) consists of multiple copies (the number varies in individuals) of a domain resembling kringle 4, a single copy of a domain resembling kringle 5, and a protease-like domain. The recently cloned hedgehog version of apolipoprotein(a), which contains 31 nearly identical copies of plasminogen kringle 3 and lacks a protease domain, has prompted us to investigate the evolutionary history of the apolipoprotein (a) gene in mammals. Our analysis supports the nonfunctionality of the human apolipoprotein(a) protease domain, and a single (or multiple) duplication of plasminogen gene before mammal radiation, which originated apolipoprotein(a) in mammals.