Abstract
The bone morphogenetic protein (BMP) type II receptor (BMPR2) has a long cytoplasmic tail domain whose function is incompletely elucidated. Mutations in the tail domain of BMPR2 are found in familial cases of pulmonary arterial hypertension. To investigate the role of the tail domain of BMPR2 in BMP signaling, we generated a mouse carrying a Bmpr2 allele encoding a non-sense mediated decay-resistant mutant receptor lacking the tail domain of Bmpr2. We found that homozygous mutant mice died during gastrulation, whereas heterozygous mice grew normally without developing pulmonary arterial hypertension. Using pulmonary artery smooth muscle cells (PaSMC) from heterozygous mice, we determined that the mutant receptor was expressed and retained its ability to transduce BMP signaling. Heterozygous PaSMCs exhibited a BMP7‑specific gain of function, which was transduced via the mutant receptor. Using siRNA knockdown and cells from conditional knockout mice to selectively deplete BMP receptors, we observed that the tail domain of Bmpr2 inhibits Alk2‑mediated BMP7 signaling. These findings suggest that the tail domain of Bmpr2 is essential for normal embryogenesis and inhibits Alk2‑mediated BMP7 signaling in PaSMCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / genetics
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Activin Receptors, Type I / metabolism
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Activin Receptors, Type II / genetics
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Activin Receptors, Type II / metabolism
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Animals
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Binding Sites / genetics
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Bone Morphogenetic Protein 4 / pharmacology
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Bone Morphogenetic Protein 7 / pharmacology*
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Bone Morphogenetic Protein Receptors, Type II / genetics*
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Cells, Cultured
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Familial Primary Pulmonary Hypertension
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Gene Expression / drug effects
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Genotype
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Hypertension, Pulmonary / genetics
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Hypertension, Pulmonary / metabolism
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Hypertension, Pulmonary / physiopathology
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Immunoblotting
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Confocal
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Muscle, Smooth, Vascular / cytology
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism
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Pulmonary Artery / cytology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion*
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Smad6 Protein / genetics
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Smad6 Protein / metabolism
Substances
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Protein 7
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Smad6 Protein
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Activin Receptors, Type I
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Activin Receptors, Type II
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Acvr1 protein, mouse
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Bmpr2 protein, mouse
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Bone Morphogenetic Protein Receptors, Type II
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activin receptor type II-A