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Abstract
Angiopoietin-2 (Ang2) is a naturally occurring antagonist of angiopoietin-1 (Ang1) that competes for binding to the Tie2 receptor and blocks Ang1-induced Tie2 autophosphorylation during vasculogenesis. Using the polymerase chain reaction, we isolated a cDNA encoding a novel shorter form of Ang2 from human umbilical vein endothelial cell cDNA and have designated it angiopoietin-2(443) (Ang2(443)), because it contains 443 amino acids. Part of the coiled-coil domain (amino acids 96-148) is absent in Ang2(443) because of alternative splicing of the gene. Like Ang2, recombinant Ang2(443) expressed in COS-7 cells is secreted as a glycosylated homodimeric protein. Recombinant Ang2(443) binds to the Tie2 receptor but does not induce Tie2 phosphorylation. Pre-occupation of Ang2(443) on Tie2 inhibits Ang1 or Ang2 binding and inhibits Ang1-induced phosphorylation. Expression of Ang2(443) mRNA is detectable in primary endothelial cells, several nonendothelial tumor cell lines, and primary tumor tissues. Interestingly, two cervical carcinoma cell lines express relatively moderate levels of Ang2(443) mRNA and protein. Macrophages express mainly Ang2 mRNA, but the expression of Ang2(443) mRNA is temporarily up-regulated during macrophage differentiation. These results suggest that Ang2(443) is a functional antagonist of Ang1 and could be an important regulator of angiogenesis during some tumorigenic and inflammatory processes.
Highlights
The recent discovery of angiopoietin-1 (Ang1)1 and angiopoietin-2 (Ang2) has provided insight into the molecular and cellular mechanisms of blood vessel formation (1, 2)
Expression of Ang2443 mRNA is detectable in primary endothelial cells, several nonendothelial tumor cell lines, and primary tumor tissues
Whereas Ang1 mRNA is mainly present in periendothelial cells, including vascular smooth muscle cells (1, 3), Ang2 mRNA is mainly present in endothelial cells (2)
Summary
Angiopoietin; PCR, polymerase chain reaction; Ang2443, angiopoietin-2443; bp, base pair(s); CHAPS, 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate; PAGE, polyacrylamide gel electrophoresis; HUVEC, human umbilical vein endothelial cell; RT, reverse transcriptase; RPA, RNase protection assay; VEGF, vascular endothelial growth factor. Valenzuela et al (6) recently isolated a novel subfamily of angiopoietins and named them mouse angiopoietin-3 (Ang3) and human angiopoietin-4 (Ang4); the two are probably interspecies orthologs and represent a third protein that binds to the Tie receptor. Angiopoietin-related protein-1 and -2 induce sprouting activity in endothelial cells but do not bind to either the Tie or Tie receptor (8). We isolated a cDNA encoding a novel alternatively spliced form of Ang from human umbilical vein endothelial cell (HUVEC) cDNA and have designated it angiopoietin-2443 (Ang2443). Our findings suggest that Ang2443 is a secreted homodimeric glycoprotein, and it may act as a functional antagonist of Ang in the regulation of angiogenesis in tumor and inflammatory cells
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