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.
Highlights
Bone morphogenetic proteins (BMPs) were initially identified as signaling factors involved in the formation of bone and cartilage
These findings suggest that Bmpr2Δtd/+ mice do not spontaneously develop pulmonary arterial hypertension (PAH)
The protein expressed by the mutant allele, Bmpr2‐ΔTD, in Bmpr2Δtd/+ cells was smaller (~100 kDa) than Bmpr2‐WT (Figure 1B). These results show that the Bmpr2Δtd allele is transcribed, Bmpr2Δtd transcripts are resistant to nonsense-mediated decay (NMD), and Bmpr2‐ΔTD protein is expressed in pulmonary artery smooth muscle cells (PaSMC)
Summary
Bone morphogenetic proteins (BMPs) were initially identified as signaling factors involved in the formation of bone and cartilage. BMPs are known to participate in a broad spectrum of biological activities during embryogenesis and organogenesis, as well as in the homeostasis of mature organs [1,2]. BMPs are members of the transforming growth factor beta family. BMPs bind to heterotetrameric receptor complexes formed by BMP type 2 and BMP type 1 serine–threonine kinases. Upon assembly of the BMP receptor complex by a BMP ligand, the constitutively active type 2 receptor phosphorylates the type 1 receptor, which in turn activates cytoplasmic BMP-responsive Smad signaling molecules— Smads 1, 5, and 8. Phosphorylated BMP-responsive Smads interact with Smad and translocate into the nucleus, where they modulate the transcription of BMP-responsive genes, such as Id1 and Smad6 [2,3,4]
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