Betacellulin induces angiogenesis through activation of mitogen-activated protein kinase and phosphatidylinositol 3'-kinase in endothelial cell.
Betacellulin (BTC) is a member of the epidermal growth factor (EGF) family, and it acts through EGF receptors. We asked whether BTC could be an angiogenic factor. Using human umbilical vein endothelial cells (HUVECs), we examined the effect of BTC on kinases and angiogenic processes. BTC induced ERK1/2 and Akt phosphorylation in a dose- and time-dependent manner. BTC induced phosphorylation of all three EGF receptors present on HUVECs: ErbB2, ErbB3, and ErbB4. Pretreatment with effective concentrations of ErbB1 inhibitor did not suppress BTC-induced kinase phosphorylation. BTC, EGF, VEGF (all at 10 ng/ml) produced similar increases in DNA synthesis. BTC, EGF, and VEGF all significantly increased endothelial cell migration. In addition, BTC promoted survival in a dose-dependent manner, and its effect was inhibited by pretreatment with PtdIns 3'-kinase inhibitor wortmannin or MEK1/2 inhibitor PD98059. Both BTC and EGF produced similar increases in tube formation in collagen gels. BTC-induced tube formation was suppressed by PD98059, wortmannin, and LY294002. In the mouse Matrigel plug assay, BTC (100 ng/ml) promoted neovessel formation, and its effect was suppressed by a combination of wortmannin and PD98059. Taken together, these data show that BTC exerts potent angiogenic activity through activation of EGF receptors, mitogen-activated protein kinase, and PtdIns 3'-kinase/Akt in endothelial cells.
Kim
Hoe Suk
HS
National Creative Research Initiatives Center for Endothelial Cells and Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
Shin
Hyoung Seek
HS
Kwak
Hee Jin
HJ
Cho
Chung-Hyun
CH
Lee
Chin O
CO
Koh
Gou Young
GY
D066259:Betacellulin; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4
D066259:Betacellulin; D004247:DNA; D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587851:BTC protein, human; C587852:Btc protein, mouse; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C494918:AKT1 protein, human