FAS1 domain protein inhibits VEGF165-induced angiogenesis by targeting the interaction between VEGFR-2 and αvβ3 integrin.
It is known that VEGF receptors (VEGFR) and integrins interact with each other to regulate angiogenesis. We reported previously that the fasciclin 1 (FAS1) domain-containing protein, TGFBIp/βig-h3 (TGF-β-induced protein) is an angiogenesis regulator that inhibits both endothelial cell migration and growth via αvβ3 integrin. In an attempt to target the interaction between VEGFR-2 and αvβ3 integrin, we determined whether the FAS1 domain region of TGFBIp/βig-h3 (FAS1 domain protein) can block the interaction between the two receptors, leading to the suppression of angiogenesis. In this study, we showed that FAS1 domain protein inhibits VEGF165-induced endothelial cell proliferation and migration via αvβ3 integrin, resulting in the inhibition of VEGF165-induced angiogenesis. We also defined a molecular mechanism by which FAS1 domain protein blocks the association between αvβ3 integrin and VEGFR-2, showing that it binds to αvβ3 integrin but not to VEGFR-2. Blocking the association of these major angiogenic receptors with FAS1 domain protein inhibits signaling pathways downstream of VEGFR-2. Collectively, our results indicate that FAS1 domain protein, in addition to its inhibitory effect on αvβ3 integrin-mediated angiogenesis, also inhibits VEGF165-induced angiogenesis. Thus, FAS1 domain protein can be further developed into a potent anticancer drug that targets two principal angiogenic pathways.
Department of Ecological Environment Conservation, Kyungpook National University, Gyeongsangbuk-do, Seoul, Korea.
Ju-Ock
JO
Nam
Hye-Nam
HN
Son
Eunsung
E
Jun
Kiweon
K
Cha
Byung-Heon
BH
Lee
Rang-Woon
RW
Park
In-San
IS
Kim
D002465:Cell Movement; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000737:chemistry / Q000378:metabolism; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D019014:fas Receptor; D000099222:betaIG-H3 Protein; C491901:FAS protein, human; C467484:VEGFA protein, human