CD36-TSP-HRGP interactions in the regulation of angiogenesis.
Thrombospondin (TSP)-1 and -2 are potent inhibitors of angiogenesis in vivo and of microvascular endothelial cell responses to angiogenic factors in vitro. The anti-angiogenic activity of thrombospondins is contained in a structural domain known as the TSP type I repeat or TSR. TSR domains are present in many other proteins, several of which have also been shown to have anti-angiogenic activity and a peptide-mimetic drug based on the domain is in clinical trials as an anti-angiogenic anti-cancer therapy. We have identified CD36 as the endothelial cell receptor for TSP-1 and -2 and showed that it is necessary for their anti-angiogenic activity. CD36-mediated anti-angiogenic activity in endothelial cells is due to its ability to activate a specific signaling cascade that results in diversion of a pro-angiogenic response to an apoptotic response. Recently we identified a circulating protein, histidine-rich glycoprotein (HRGP), that contains a CD36 homology domain and that acts as a soluble decoy to block the anti-angiogenic activities of TSPs, thereby promoting angiogenesis. The tripartite interactions among CD36, TSR domains and HRGP in tissues may play an important role in regulating physiological and pathological angiogenesis.
Silverstein
Roy L
RL
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. silverr2@ccf.org
Febbraio
Maria
M
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018955:CD36 Antigens / Q000737:chemistry / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism*; D019699:Thrombospondins / Q000737:chemistry / Q000378:metabolism*; D000099053:Histidine-Rich Glycoprotein; D000099262:Thrombospondin 2
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018955:CD36 Antigens; D011506:Proteins; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099053:Histidine-Rich Glycoprotein; D000099262:Thrombospondin 2