Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension

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DOIResolve DOI: http://doi.org/10.1152/ajplung.00300.2010
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TypeArticle
Journal titleAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
ISSN1040-0605
Volume301
Issue2
PagesL218L227
Subjectbone morphogenetic protein receptor; bone morphogenetic protein receptor 2; clathrin; Smad protein; animal cell; article; caveola; cell membrane; mouse; mutant; nonhuman; priority journal; protein expression; protein localization; protein phosphorylation; pulmonary hypertension; Animals; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Caveolae; Cell Line; Cell Membrane; Coated Pits, Cell-Membrane; Humans; Hypertension, Pulmonary; Mutation; Phosphorylation; Signal Transduction; Smad Proteins; Tissue Distribution; Up-Regulation
AbstractBone morphogenetic proteins (BMPs) are pleiotrophic growth factors that influence diverse processes such as skeletal development, hematopoiesis, and neurogenesis. They play crucial roles in diseases such as pulmonary arterial hypertension (PAH). In PAH, mutants of the BMP type II receptors (BMPR2) were detected, and their functions were impaired during BMP signaling. It is thought that expression levels of these receptors determine the fate of BMP signaling, with low levels of expression leading to decreased Smad activation in PAH. However, our studies demonstrate, for the first time, that the localization of receptors on the plasma membrane, in this case BMPR2, was misdirected. Three BMPR2 mutants, D485G, N519K, and R899X, which are known to be involved in PAH, were chosen as our model system. Our results show that all three BMPR2 mutants decreased BMP-dependent Smad phosphorylation and Smad signaling. Although the three mutants reached the cell membrane and their expression was lower than that of BMPR2, they formed smaller clusters and associated differently with membrane domains, such as caveolae and clathrin-coated pits. The disruption of these domains restored the Smad signaling of D485G and N519K to the level of wild-type BMPR2, showing that these mutants were trapped in the domains, rather than just expressed at a lower level on the surface. Therefore, new treatment options for PAH should also target receptor localization, rather than just expression level. © 2011 the American Physiological Society.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); National Institute for Nanotechnology (NINT-INNT)
Peer reviewedYes
NPARC number21271382
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Record identifier8a96b271-7c7a-4615-b4d3-d703d8c9bccc
Record created2014-03-24
Record modified2016-05-09
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