Inhibition of the mitogenic, angiogenic and tumorigenic activities of pleiotrophin by a synthetic peptide corresponding to its C-thrombospondin repeat-I domain.
Pleiotrophin (PTN), is a heparin-dependent growth factor involved in angiogenesis and tumor growth. PTN contains a thrombospondin repeat-I (TSR-I) motif in its two beta-sheet domains that are involved in its binding to heparin and its neurite outgrowth activity. Based on the importance of the binding of PTN to heparin in its dimerization and biological activities, we have designed two synthetic peptides, P(13-39) and P(65-97) corresponding to a part of the N-terminal and C-terminal TSR-I motif of PTN, respectively. P(65-97) inhibited the mitogenic, tumorigenic and angiogenic activities of PTN, as well as the mitogenic and an angiogenic activity of fibroblast growth factor-2 (FGF-2). However, P(65-97) had no effect on the mitogenic activity of epidermal growth factor, which does not bind heparin. P(65-97) but not P(13-39) inhibited the binding of PTN and to a lesser extent of FGF-2 to heparin using an immunoassay and an optical biosensor assay and bound directly to heparin with a K(d) of 120 nM. These findings suggest that P(65-97), containing amino acids 65-97 of the TSR-I motif of the C-terminal domain of PTN, inhibits the activities of PTN and FGF-2 by virtue of its ability to bind heparin very effectively and so compete with the growth factors for their polysaccharide co-receptor.
Hamma-Kourbali
Yamina
Y
Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), CNRS UMR 7149, Université Paris XII, Créteil Cedex, France.
Bernard-Pierrot
Isabelle
I
Heroult
Mélanie
M
Dalle
Sophie
S
Caruelle
Danièle
D
Milhiet
Pierre Emmanuel
PE
Fernig
David G
DG
Delbé
Jean
J
Courty
José
J
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D006493:Heparin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D019699:Thrombospondins / Q000737:chemistry*; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology
D002352:Carrier Proteins; D016207:Cytokines; D010455:Peptides; D011994:Recombinant Proteins; D019699:Thrombospondins; D016222:Fibroblast Growth Factor 2; C066845:pleiotrophin; D006493:Heparin