title: Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins.
abstract: Tumstatin and endostatin are two inhibitors of angiogenesis derived from precursor human collagen molecules known as alpha 3 chain of type IV collagen and alpha1 chain of type XVIII collagen, respectively. Although both these inhibitors are noncollagenous (NC1) domain fragments of collagens, they only share a 14% amino acid homology. In the present study we evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these two collagen-derived inhibitors. Human tumstatin prevents angiogenesis via inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas human endostatin prevents endothelial cell migration with no effect on proliferation. We demonstrate that human tumstatin binds to alpha v beta 3 integrin in a vitronectin/fibronectin/RGD cyclic peptide independent manner, whereas human endostatin competes with fibronectin/RGD cyclic peptide to bind alpha 5 beta 1 integrin. The activity of human tumstatin is mediated by alpha v beta 3 integrin, whereas the activity of human endostatin is mediated by alpha 5 beta 1 integrin. Additionally, although human tumstatin binding to alpha v beta 3 integrin leads to the inhibition of Cap-dependent translation (protein synthesis) mediated by focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway, human endostatin binding to alpha 5 beta 1 integrin leads to the inhibition of focal adhesion kinase/c-Raf/MEK1/2/p38/ERK1 mitogen-activated protein kinase pathway, with no effect on phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 and Cap-dependent translation. Collectively, such distinct properties of human tumstatin and human endostatin provide the first insight into their diverse antiangiogenic actions and argue for combining them for targeting tumor angiogenesis.
authors.affiliation: Program in Matrix Biology, Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Akulapalli
authors.initials: A
authors.lastname: Sudhakar
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Changqing
authors.initials: C
authors.lastname: Yang
authors.forename: Julie
authors.initials: J
authors.lastname: Lively
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001667:Binding, Competitive; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D024141:Collagen Type IV / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D043170:Collagen Type XVIII; D043169:Endostatins; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D039081:Integrin alpha5beta1 / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control*; D009842:Oligopeptides; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D019096:Vitronectin / Q000378:metabolism
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D043170:Collagen Type XVIII; D043169:Endostatins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019096:Vitronectin; C057112:type IV collagen alpha3 chain; C047981:arginyl-glycyl-aspartic acid; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human