Biological activities of peptides and peptide analogues derived from common sequences present in thrombospondin, properdin, and malarial proteins.
Thrombospondin (TSP), a major platelet-secreted protein, has recently been shown to have activity in tumor cell metastasis, cell adhesion, and platelet aggregation. The type 1 repeats of TSP contain two copies of CSVTCG and one copy of CSTSCG, per each of the three polypeptide chains of TSP and show homology with peptide sequences found in a number of other proteins including properdin, malarial circumsporozoite, and a blood-stage antigen of Plasmodium falciparum. To investigate whether these common sequences functioned as a cell adhesive domain in TSP, we assessed the effect of peptides corresponding to these sequences and an antibody raised against one of these sequences, CSTSCG, in three biological assays which depend, in part, on the cell adhesive activity of TSP. These assays were TSP-dependent cell adhesion, platelet aggregation, and tumor cell metastasis. We found that a number of peptides homologous to CSVTCG promoted the adhesion of a variety of cells including mouse B16-F10 melanoma cells, inhibited platelet aggregation and tumor cell metastasis, whereas control peptides had no effect. Anti-CSTSCG, which specifically recognized TSP, inhibited TSP-dependent cell adhesion, platelet aggregation, and tumor cell metastasis, whereas control IgG had no effect. These results suggest that CSVTCG and CSTSCG present in the type I repeats function in the adhesive interactions of TSP that mediate cell adhesion, platelet aggregation, and tumor cell metastasis. Peptides, based on the structure of these repeats, may find wide application in the treatment of thrombosis and in the prevention of cancer spread.
Tuszynski
G P
GP
Department of Medicine, Medical College of Pennsylvania, Philadelphia 19129.
Rothman
V L
VL
Deutch
A H
AH
Hamilton
B K
BK
Eyal
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011414:Properdin / Q000235:genetics / Q000502:physiology*; D015800:Protozoan Proteins; D012689:Sequence Homology, Nucleic Acid; D013329:Structure-Activity Relationship; D019699:Thrombospondins
D000953:Antigens, Protozoan; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D015800:Protozoan Proteins; D019699:Thrombospondins; C041595:circumsporozoite protein, Protozoan; D011414:Properdin