title: Peptides derived from type I thrombospondin repeat-containing proteins of the CCN family inhibit proliferation and migration of endothelial cells.
abstract: Angiogenesis, or neovascularization, is tightly orchestrated by endogenous regulators that promote or inhibit the process. The fine-tuning of these pro- and anti-angiogenic elements (the angiogenic balance) helps establish the homeostasis in tissues, and any aberration leads to pathologic conditions. The type I thrombospondin repeats are a family of protein structural elements involved in the control of angiogenesis, and some proteins containing these repeats have been identified as negative regulators of angiogenesis. Here we identify a set of 11 novel, anti-angiogenic 18-20-amino acid peptides that are derived from proteins that belong to the CCN protein family and contain type I thrombospondin motifs. We have named these peptides spondinstatin-1, cyrostatin, connectostatin, nephroblastostatin, wispostatin-2, wispostatin-3, netrinstatin-5C, netrinstatin-5D, adamtsostatin-like-4, fibulostatin-6.1, and complestatin-C6 to reflect their origin. We have shown that these peptides inhibit proliferation and migration of human umbilical vein endothelial cells in vitro. By conducting a clustering analysis of the amino acid sequences using sequence similarity criteria and of the experimental results using a hierarchical clustering algorithm, we have demonstrated that there is an underlying correlation between the sequence and activity of the identified peptides. This combination of experimental and computational approaches introduces a novel systematic framework for studying peptide activity, identifying novel peptides with anti-angiogenic activity, and designing mimetic peptides with tailored properties.
authors: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. ekaragi1@jhmi.edu
authors: Emmanouil D
authors: ED
authors: Karagiannis
authors: Aleksander S
authors: AS
authors: Popel
mesh_terms: D000071096:ADAMTS Proteins; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D055511:CCN Intercellular Signaling Proteins; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016000:Cluster Analysis; D003183:Complement C6 / Q000737:chemistry; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry; D007136:Immunoglobulins / Q000737:chemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D000075386:Netrin Receptors; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000737:chemistry; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D019700:Thrombospondin 1 / Q000737:chemistry*; D019699:Thrombospondins / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry
chemical_list: C486779:ADAMTSL4 protein, human; D020533:Angiogenesis Inhibitors; D055511:CCN Intercellular Signaling Proteins; C501848:CCN1 protein, human; C526317:CCN2 protein, human; C413323:CCN5 protein, human; C400081:CCN6 protein, human; D003183:Complement C6; D055515:Cysteine-Rich Protein 61; C488168:HMCN1 protein, human; D017874:Immediate-Early Proteins; D007136:Immunoglobulins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000075386:Netrin Receptors; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D019700:Thrombospondin 1; D019699:Thrombospondins; D014157:Transcription Factors; C115727:UNC5C protein, human; D055513:Connective Tissue Growth Factor; D000071096:ADAMTS Proteins
references: Ann N Y Acad Sci. 1999;886:58-66
references: 10667203
references: Biochem Biophys Res Commun. 2007 Mar 9;354(2):434-9
references: 17239819
references: Biochem Biophys Res Commun. 2000 Aug 18;275(1):108-14
references: 10944450
references: J Pharmacol Toxicol Methods. 2000 Jan-Feb;43(1):15-24
references: 11091126
references: Cancer Metastasis Rev. 2000;19(1-2):159-65
references: 11191055
references: Int J Cancer. 2002 Apr 10;98(5):682-9
references: 11920636
references: J Cell Mol Med. 2002 Jan-Mar;6(1):1-12
references: 12003665
references: Cancer Res. 2002 Aug 15;62(16):4678-84
references: 12183425
references: Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8
references: 12516034
references: J Biol Chem. 2003 Jun 27;278(26):24200-8
references: 12695522
references: Angiogenesis. 2002;5(3):153-65
references: 12831056
references: Mol Cell Biol. 2003 Aug;23(15):5401-8
references: 12861025
references: J Endocrinol. 2003 Aug;178(2):169-75
references: 12904165
references: J Biol Chem. 2003 Sep 26;278(39):37849-57
references: 12867428
references: Int Rev Cytol. 2003;230:1-39
references: 14692680
references: Bioinformatics. 2004 Feb 12;20(3):426-7
references: 14960472
references: Int J Biochem Cell Biol. 2004 Jun;36(6):981-5
references: 15094112
references: Int J Biochem Cell Biol. 2004 Jun;36(6):1070-8
references: 15094121
references: DNA Cell Biol. 2004 Jun;23(6):367-79
references: 15231070
references: Harvey Lect. 1996-1997;92:65-82
references: 15372744
references: J Biol Chem. 2004 Oct 1;279(40):41734-43
references: 15292271
references: Cancer Res. 2004 Oct 15;64(20):7420-5
references: 15492265
references: Blood. 1992 Sep 1;80(5):1105-15
references: 1381234
references: J Cell Biol. 1993 Jul;122(2):497-511
references: 7686555
references: Stat Methods Med Res. 1992;1(1):27-48
references: 1341650
references: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references: 7984417
references: Nat Med. 1995 Jan;1(1):27-31
references: 7584949
references: Biol Pharm Bull. 1996 Nov;19(11):1518-20
references: 8951178
references: Cell. 1997 Jan 24;88(2):277-85
references: 9008168
references: Cancer Res. 1997 May 1;57(9):1735-42
references: 9135017
references: J Cell Biol. 1997 Aug 11;138(3):707-17
references: 9245797
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6355-60
references: 9600969
references: Mol Pharmacol. 1999 Feb;55(2):332-8
references: 9927626
references: J Biochem. 1999 Jul;126(1):137-45
references: 10393331
references: J Biol Chem. 1999 Aug 13;274(33):23349-57
references: 10438512
references: J Biol Chem. 1999 Aug 20;274(34):24080-6
references: 10446179
references: Nature. 2004 Nov 11;432(7014):179-86
references: 15510105
references: APMIS. 2004 Jul-Aug;112(7-8):496-507
references: 15563312
references: Biochem J. 2005 Feb 15;386(Pt 1):15-27
references: 15554875
references: J Cell Biol. 2005 Feb 14;168(4):643-53
references: 15716381
references: J Med Chem. 2005 Apr 21;48(8):2838-46
references: 15828822
references: Cancer Res. 2005 May 1;65(9):3656-63
references: 15867360
references: Cancer Res. 2005 May 15;65(10):3967-79
references: 15899784
references: Trends Mol Med. 2005 Jul;11(7):336-40
references: 15961345
references: Cancer Res. 2005 Dec 1;65(23):11044-50
references: 16322254
references: Nature. 2005 Dec 15;438(7070):932-6
references: 16355210
references: Biochim Biophys Acta. 2006 Apr;1765(2):178-88
references: 16406676
references: Dev Dyn. 2000 Jun;218(2):280-99
references: 10842357