BMPER, a Novel Endothelial Cell Precursor-Derived Protein, Antagonizes Bone Morphogenetic Protein Signaling and Endothelial Cell Differentiation

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.

von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

“…In vitro, CV2 at excessive doses inhibited the BMP-dependent differentiation of osteoblast and chondrocyte in cell culture (25). The transfection of 293T cells with a CV2 cDNA-containing plasmid reduced cellular response to BMP-4 in a BMP-responding luciferase reporter assay (43). These results are consistent with our observation that excessive doses of CV2 inhibited BMP-2-induced ALP activity.…”

OC29 is preferentially expressed in the presumptive sensory organ region of the otocyst

“…Based on this knowledge and our in situ hybridization results, showing the colocalization of the signals of OC29 and BMP4, we hypothesize that OC29 might also bind and regulate BMP4. However, our coimmunoprecipitation experiments performed as described (Hill et al, 2003;Moser et al, 2003) have failed to identify any interaction with BMP4, as BMP2 and BMP7.…”

Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells

“…Furthermore, it has a role in EC differentiation; BMP-binding endothelial cell precursor-derived regulator, a recently described BMP antagonist in EC, inhibits both BMP signaling and EC differentiation (49). BMP-2 has been implicated in angiogenesis through osteoblast-derived VEGF-A (50), and BMP-2 stimulated angiogenesis has been reported in developing tumors (51).…”