Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking alphavbeta5 integrin.
Brain-specific angiogenesis inhibitor 1 (BAI1) is a transmembrane protein with anti-angiogenic activity. The mechanisms underlying BAI1 activity are unknown. In this study, we found that overexpression of BAI1 increased cell death in human umbilical vein endothelial cells (HUVECs) and, to a lesser degree, in SHSY5Y and U343 cells. Conditioned medium from BAI1-transfected U343 cells inhibited proliferation of HUVECs, and this effect was neutralized by addition of anti-BAI1 serum. The conditioned medium contained four cleavage products of the BAI1 extracellular domain. BAI1's middle extracellular region containing five thrombospondin type 1 repeats (BAI1-TSR) was sufficient for BAI1's antiproliferative effect on HUVECs. BAI1's action on HUVECs was blocked by anti-alpha(v) integrin, but not by anti-CD36 antibody treatment. Introduction of alpha(v)beta(5) integrin into HEK293 cells rendered them susceptible to cell death by BAI1, and BAI1-TSR bound with alpha(v)beta(5) integrin, but not to alpha(v)beta(3) integrin in brain tissue. Fluorescent BAI1-TSR colocalized with alpha(v)beta(5) integrin in HUVECs. Together, our results indicate that BAI1 has antiproliferative action on surrounding endothelial cells by blocking alpha(v)beta(5) integrin, and its active region is BAI1-TSR. BAI1-TSR could be valuable for regulating brain angiogenesis.
Dental Science Research Institute, Chonnam National University, Kwangju 501-190, South Korea. kimkk@chonnam.ac.kr
Jeong Tae
JT
Koh
Hyun
H
Kook
Hae Jin
HJ
Kee
Young-Woo
YW
Seo
Byung Chul
BC
Jeong
Ji Hee
JH
Lee
Mi-Young
MY
Kim
Kyung Chul
KC
Yoon
Shin
S
Jung
Kyung Keun
KK
Kim
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D018955:CD36 Antigens / Q000276:immunology; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D039564:Integrin alphaV / Q000276:immunology; D016023:Integrins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D009336:Necrosis; D010446:Peptide Fragments / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled; D019030:Receptors, Vitronectin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
C468226:ADGRB1 protein, human; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D018955:CD36 Antigens; D061945:Caspase Inhibitors; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; D039564:Integrin alphaV; D016023:Integrins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5