BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation

Mol Cell Biol. 2003 Aug;23(16):5664-79. doi: 10.1128/MCB.23.16.5664-5679.2003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blotting, Northern
  • Blotting, Western
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • COS Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / pharmacology*
  • Cell Differentiation
  • Cell Line
  • Cloning, Molecular
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / metabolism
  • Endothelium, Vascular / metabolism
  • Flow Cytometry
  • Gene Library
  • Genes, Reporter
  • Humans
  • In Situ Hybridization
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Phosphoproteins / metabolism
  • Polymerase Chain Reaction
  • Precipitin Tests
  • Protein Structure, Tertiary
  • RNA / metabolism
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad5 Protein
  • Time Factors
  • Tissue Distribution
  • Trans-Activators / metabolism
  • Transfection
  • Transforming Growth Factor beta*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenopus Proteins
  • Xenopus laevis

Substances

  • BMP2 protein, human
  • BMP4 protein, human
  • BMP6 protein, human
  • BMPER protein, human
  • Bmp2 protein, mouse
  • Bmp4 protein, mouse
  • Bmp6 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Recombinant Proteins
  • SMAD5 protein, human
  • Smad5 Protein
  • Smad5 protein, Xenopus
  • Smad5 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • bmp4 protein, Xenopus
  • recombinant human bone morphogenetic protein-2
  • RNA
  • Vascular Endothelial Growth Factor Receptor-2