Adhesion-GPCRs pp 167-178 | Cite as

Emerging Roles of Brain-Specific Angiogenesis Inhibitor 1

  • Daeho Park
  • Kodi S. Ravichandran
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 706)


Brain-specific angiogenesis inhibitor 1 (BAI1) encodes a seven-transmembrane protein that belongs to the adhesion-GPCR family.1, 2, 3, 4, 5, 6, 7 Although BAI1 was named for the ability of its extracellular region to inhibit angiogenesis in tumor models, its function in physiological contexts was elusive and remained an orphan receptor until recently.5,6,8, 9, 10, 11, 12, 13, 14 BAI1 is now considered a phagocytic receptor that can recognize phosphatidylserine exposed on apoptotic cells. Moreover, BAI1 has been shown to function upstream of the signaling module comprised of ELMO/Dock180/Rac proteins, thereby facilitating the cytoskeletal reorganization necessary to mediate the phagocytic clearance of apoptotic cells.15,16 Here,wereview the phytogeny, structure, associating proteins, as well as the known and proposed functions of BAI1.


Apoptotic Cell Cytoplasmic Tail U373MG Cell Extracellular Region Thrombospondin Type 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Kee HJ, Ahn KY, Choi KC et al. Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma. FEBS Lett 2004; 569(1-3):307–316.PubMedCrossRefGoogle Scholar
  2. 2.
    Kaur B, Brat DJ, Calkins CC et al. Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 2003; 162(1):19–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Mori K, Kanemura Y, Fujikawa H et al. Brain-specific angiogenesis inhibitor 1 (BAI1) is expressed in human cerebral neuronal cells. Neurosci Res 2002; 43(1):69–74.PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshida Y, Oshika Y, Fukushima Y et al. Expression of angiostatic factors in colorectal cancer. Int J Oncol 1999; 15(6):1221–1225.PubMedGoogle Scholar
  5. 5.
    Fukushima Y, Oshika Y, Tsuchida T et al. Brain-specific angiogenesis inhibitor 1 expression is inversely correlated with vascularity and distant metastasis of colorectal cancer. Int J Oncol 1998; 13(5):967–970.PubMedGoogle Scholar
  6. 6.
    Nishimori H, Shiratsuchi T, Urano T et al. A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 1997; 15(18):2145–2150.PubMedCrossRefGoogle Scholar
  7. 7.
    Shiratsuchi T, Nishimori H, Ichise H et al. Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenet Cell Genet 1997; 79(1-2): 103–108.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaur B, Cork SM, Sandberg EM et al. Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis througha CD36-dependent mechanism. Cancer Res 2009; 69(3):1212–1220.PubMedCrossRefGoogle Scholar
  9. 9.
    Kudo S, Konda R, Obara W et al. Inhibition of tumor growth through suppression of angiogenesis by brain-specific angiogenesis inhibitor 1 gene transfer in murine renal cell carcinoma. Oncol Rep 2007; 18(4):785–791.PubMedGoogle Scholar
  10. 10.
    Kang X, Xiao X, Harata M et al. Antiangiogenic activity of BAI1 in vivo: implications for gene therapy of human glioblastomas. Cancer Gene Ther 2006; 13(4):385–392.PubMedCrossRefGoogle Scholar
  11. 11.
    Kaur B, Brat DJ, Devi NS et al. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 2005; 24(22):3632–3642.PubMedCrossRefGoogle Scholar
  12. 12.
    Yoon KC, Ahn KY, Lee JH et al. Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model. Gene Ther 2005; 12(7):617–624.PubMedCrossRefGoogle Scholar
  13. 13.
    Koh JT, Kook H, Kee HJ et al. Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking alphavbeta5 integrin. Exp Cell Res 2004; 294(1):172–184.PubMedCrossRefGoogle Scholar
  14. 14.
    Hatanaka H, Oshika Y, Abe Y et al. Vascularization is decreased in pulmonary adenocarcinoma expressing brain-specific angiogenesis inhibitor 1 (BAI1). Int J Mol Med 2000; 5(2):181–183.PubMedGoogle Scholar
  15. 15.
    Park D, Hochreiter-Hufford A, Ravichandran KS. The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr Biol 2009; 19(4):346–351.PubMedCrossRefGoogle Scholar
  16. 16.
    Park D, Tosello-Trampont AC, Elliott MR et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 2007; 450(7168):430–434.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature 2009; 459(7245):356–363.PubMedCrossRefGoogle Scholar
  18. 18.
    Fredriksson R, Lagerstrom MC, Lundin LG et al. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups and fingerprints. Mol Pharmacol 2003; 63(6):1256–1272.PubMedCrossRefGoogle Scholar
  19. 19.
    Klabunde T, Hessler G. Drug design strategies for targeting G-protein-coupled receptors. Chembiochem 2002; 3(10):928–944.PubMedCrossRefGoogle Scholar
  20. 20.
    Bjarnadottir TK, Fredriksson R, Hoglund PJ et al. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics 2004; 84(1):23–33.PubMedCrossRefGoogle Scholar
  21. 21.
    Haitina T, Olsson F, Stephansson O et al. Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci 2008; 9:43.PubMedCrossRefGoogle Scholar
  22. 22.
    Yona S, Lin HH, Siu WO et al. Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci 2008; 33(10):491–500.PubMedCrossRefGoogle Scholar
  23. 23.
    Bjarnadottir TK, Fredriksson R, Schioth HB. The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. Cell Mol Life Sci 2007; 64(16):2104–2119.PubMedCrossRefGoogle Scholar
  24. 24.
    Lawler J, Hynes RO. The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol 1986; 103(5):1635–1648.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen H, Herndon ME, Lawler J. The cell biology of thrombospondin-1. Matrix Biol 2000; 19(7):597–614.PubMedCrossRefGoogle Scholar
  26. 26.
    Silverstein RL. The face of TSR revealed: an extracellular signaling domain is exposed. J Cell Biol 2002; 159(2):203–206.PubMedCrossRefGoogle Scholar
  27. 27.
    Manodori AB, Barabino GA, Lubin BH et al. Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood 2000; 95(4):1293–1300.PubMedGoogle Scholar
  28. 28.
    Adams JC, Tucker RP. The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev Dyn 2000; 218(2):280–299.PubMedCrossRefGoogle Scholar
  29. 29.
    Huwiler KG, Vestling MM, Annis DS et al. Biophysical characterization, including disulfide bond assignments, of the anti-angiogenic type 1 domains of human thrombospondin-1. Biochemistry 2002; 41(48):14329–14339.PubMedCrossRefGoogle Scholar
  30. 30.
    Smith KF, Nolan KF, Reid KB et al. Neutron and X-ray scattering studies on the human complement protein properdin provide an analysis of the thrombospondin repeat. Biochemistry 1991; 30(32):8000–8008.PubMedCrossRefGoogle Scholar
  31. 31.
    Harmar AJ. Family-B G-protein-coupled receptors. Genome Biol 2001; 2(12):REVIEWS3013.Google Scholar
  32. 32.
    Shiratsuchi T, Futamura M, Oda K et al. Cloning and characterization of BAI-associated protein 1: a PDZ domain-containing protein that interacts with BAI1. Biochem Biophys Res Commun 1998; 247(3):597–604.PubMedCrossRefGoogle Scholar
  33. 33.
    Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 2007; 7(12):964–974.PubMedCrossRefGoogle Scholar
  34. 34.
    Elliott MR, Ravichandran KS. Clearance of apoptotic cells: implications in health and disease. J Cell Biol 1059; 189(7):1059–1070.CrossRefGoogle Scholar
  35. 35.
    Elliott MR, Zheng S, Park D et al. Unexpected requirement for ELMO1 in apoptotic germ cell clearance in vivo. Nature 2010; In Press.Google Scholar
  36. 36.
    Park D, Tosello-Trampont AC, Elliott MR et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 2007; 450:430–434.PubMedCrossRefGoogle Scholar
  37. 37.
    Lu M, Ravichandran KS. Dock180-ELMO cooperation in Rac activation. Methods Enzymol 2006; 406:388–402.PubMedCrossRefGoogle Scholar
  38. 38.
    Lu M, Kinchen JM, Rossman KL et al. A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs. Curr Biol 2005; 15(4):371–377.PubMedCrossRefGoogle Scholar
  39. 39.
    Lu M, Kinchen JM, Rossman KL et al. PH domain of ELMO functions in trans to regulate Rac activation via Dock180. Nat Struct Mol Biol 2004; 11(8):756–762.PubMedCrossRefGoogle Scholar
  40. 40.
    Grimsley CM, Kinchen JM, Tosello-Trampont AC et al. Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration. J Biol Chem 2004; 279(7):6087–6097.PubMedCrossRefGoogle Scholar
  41. 41.
    Brugnera E, Haney L, Grimsley C et al. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 2002; 4(8):574–582.PubMedGoogle Scholar
  42. 42.
    Gumienny TL, Brugnera E, Tosello-Trampont AC et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 2001; 107(1):27–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med 2008; 10:e23.PubMedCrossRefGoogle Scholar
  44. 44.
    Kleihues P, Louis DN, Scheithauer BW et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002; 61(3):215–225; discussion 226–219.PubMedGoogle Scholar
  45. 45.
    Duda DG, Sunamura M, Lozonschi L et al. Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis. Br J Cancer 2002; 86(3):490–496.PubMedCrossRefGoogle Scholar
  46. 46.
    Cao Y, Nagesh V, Hamstra D et al. The extent and severity of vascular leakage as evidence of tumor aggressiveness in high-grade gliomas. Cancer Res 2006; 66(17):8912–8917.PubMedCrossRefGoogle Scholar
  47. 47.
    Muccio CF, Esposito G, Bartolini A et al. Cerebral abscesses and necrotic cerebral tumours: differential diagnosis by perfusion-weighted magnetic resonance imaging. Radiol Med 2008; 113(5):747–757.PubMedCrossRefGoogle Scholar
  48. 48.
    Ray SK, Patel SJ, Welsh CT et al. Molecular evidence of apoptotic death inmalignant brain tumors including glioblastoma multiforme: upregulation of calpain and caspase-3. J Neurosci Res 2002; 69(2):197–206.PubMedCrossRefGoogle Scholar
  49. 49.
    Sinha S, Bastin ME, Whittle IR et al. Diffusion tensor MR imaging of high-grade cerebral gliomas. AJNR Am J Neuroradiol 2002; 23(4):520–527.PubMedGoogle Scholar
  50. 50.
    Fujiwara T, Mammoto A, Kim Y et al. Rho small G-protein-dependent binding of mDia to an Src homology 3 domain-containing IRSp53/BAIAP2. Biochem Biophys Res Commun 2000; 271(3):626–629.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim MY, Ahn KY, Lee SM et al. The promoter of brain-specific angiogenesis inhibitor 1-associated protein 4 drives developmentally targeted transgene expression mainly in adult cerebral cortex and hippocampus. FEBS Lett 2004; 566(1-3):87–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Oda K, Shiratsuchi T, Nishimori H et al. Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1. Cytogenet Cell Genet 1999; 84(1-2):75–82.PubMedCrossRefGoogle Scholar
  53. 53.
    Shiratsuchi T, Oda K, Nishimori H et al. Cloning and characterization of BAP3 (BAI-associatedprotein 3), a C2 domain-containingproteinthat interacts with BAI1. Biochem Biophys Res Commun 1998; 251(1):158–165.PubMedCrossRefGoogle Scholar
  54. 54.
    Koh JT, Lee ZH, Ahn KY et al. Characterization of mouse brain-specific angiogenesis inhibitor 1 (BAI1) and phytanoyl-CoA alpha-hydroxylase-associated protein 1, a novel BAI1-binding protein. Brain Res Mol Brain Res 2001; 87(2):223–237.PubMedCrossRefGoogle Scholar
  55. 55.
    Funke L, Dakoji S, Bredt DS. Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem 2005; 74:219–245.PubMedCrossRefGoogle Scholar
  56. 56.
    Gonzalez-Mariscal L, Betanzos A, Avila-Flores A. MAGUK proteins: structure and role in the tight junction. Semin Cell Dev Biol 2000; 11(4):315–324.PubMedCrossRefGoogle Scholar
  57. 57.
    Krugmann S, Jordens I, Gevaert K et al. Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex. Curr Biol 2001; 11(21):1645–1655.PubMedCrossRefGoogle Scholar
  58. 58.
    Miki H, Yamaguchi H, Suetsugu S et al. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 2000; 408(6813):732–735.PubMedCrossRefGoogle Scholar
  59. 59.
    Takenawa T, Miki H. WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. J Cell Sci 2001; 114(Pt 10): 1801–1809.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Daeho Park
  • Kodi S. Ravichandran
    • 1
  1. 1.Beirne Carter Center for Immunology Research and Department of MicrobiologyUniversity of VirginiaCharlottesvilleUSA

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