BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation.
The development of endothelial cell precursors is essential for vasculogenesis. We screened for differentially expressed transcripts in endothelial cell precursors in developing mouse embryoid bodies. We cloned a complete cDNA encoding a protein that contains an amino-terminal signal peptide, five cysteine-rich domains, a von Willebrand D domain, and a trypsin inhibitor domain. We termed this protein BMPER (bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator). BMPER is specifically expressed in flk-1-positive cells and parallels the time course of flk-1 induction in these cells. In situ hybridization in mouse embryos demonstrates dorsal midline staining and staining of the aorto-gonadal-mesonephric region, which is known to host vascular precursor cells. BMPER is a secreted protein that directly interacts with BMP2, BMP4, and BMP6 and antagonizes BMP4-dependent Smad5 activation. In Xenopus embryos, ventral injection of BMPER mRNA results in axis duplication and downregulation of the expression of Xvent-1 (downstream target of Smad signaling). In an embryoid body differentiation assay, BMP4-dependent differentiation of endothelial cells in embryoid bodies is also antagonized by BMPER. Taken together, our data indicate that BMPER is a novel BMP-binding protein that is expressed by endothelial cell precursors, has BMP-antagonizing activity, and may play a role in endothelial cell differentiation by modulating local BMP activity.
Moser
Martin
M
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Binder
Olav
O
Wu
Yaxu
Y
Aitsebaomo
Julius
J
Ren
Rongqin
R
Bode
Christoph
C
Bautch
Victoria L
VL
Conlon
Frank L
FL
Patterson
Cam
C
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D015723:Gene Library; D017930:Genes, Reporter; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051902:Smad5 Protein; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525816:BMP6 protein, human; C476724:BMPER protein, human; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C497797:SMAD5 protein, human; D051902:Smad5 Protein; C497800:Smad5 protein, Xenopus; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; C499469:recombinant human bone morphogenetic protein-2; D012313:RNA; D040301:Vascular Endothelial Growth Factor Receptor-2