Biological characterization of angiopoietin-3 and angiopoietin-4.
The angiopoietin (Ang) family of growth factors includes Ang1, Ang2, Ang3, and Ang4, all of which bind to the endothelial receptor tyrosine kinase Tie2. Ang3 (mouse) and Ang4 (human) are interspecies orthologs. In experiments with human endothelial cell lines, Ang3 was identified as an antagonist of Tie2 and Ang4 was identified as an agonist of Tie2. However, the biological roles of Ang3 and Ang4 are unknown. We examined the biological effect of recombinant Ang3 and Ang4 proteins in primary cultured endothelial cells and in vivo in mice. Recombinant Ang3 and Ang4 formed disulfide-linked dimers. Ang4 (400 ng/mL) markedly increased Tie2 and Akt phosphorylation in primary cultured HUVECs whereas Ang3 (400 ng/mL) did not produce significant changes. Accordingly, Ang4, but not Ang3, induced survival and migration in primary cultured HUVECs. Unexpectedly, intravenously administered Ang3 (30 microg) was more potent than Ang4 (30 microg) in phosphorylating the Tie2 receptor in lung tissue from mice in vivo. Accordingly, Ang3 was more potent than Ang4 in phosphorylating Akt in primary cultured mouse lung microvascular endothelial cells. Ang3 and Ang4 both produced potent corneal angiogenesis extending from the limbus across the mouse cornea in vivo. Thus, Ang3 and Ang4 are agonists of Tie2, but mouse Ang3 has strong activity only on endothelial cells of its own species.
Lee
Hyuek Jong
HJ
Biomedical Research Center and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Cho
Chung-Hyun
CH
Hwang
Su-Jeong
SJ
Choi
Han-Ho
HH
Kim
Kyung-Tae
KT
Ahn
So Young
SY
Kim
Ju-Hyun
JH
Oh
Jong-Lark
JL
Lee
Gyun Min
GM
Koh
Gou Young
GY
D042683:Angiopoietin-1 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D042702:Angiopoietin-2 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D000091304:Angiopoietin-Like Protein 1; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology; D002196:Capillaries / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016510:Corneal Neovascularization / Q000209:etiology*; D019281:Dimerization; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D042787:Receptor, TIE-2 / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D013045:Species Specificity; D014162:Transfection; D014471:Umbilical Veins
C467630:ANGPT1 protein, human; C117578:ANGPTL1 protein, human; C403682:Ang3 protein, mouse; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000091304:Angiopoietin-Like Protein 1; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001798:Blood Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C118117:angiopoietin 4; D042787:Receptor, TIE-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012260:Ribonucleases