Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension.

Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Research Abstract Details 

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Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Abstract Text:

Nung Rudarakanchana,Julia A Flanagan,Hailan Chen,Paul D Upton,Rajiv Machado,D Patel,Richard C Trembath,Nicholas W Morrell,

A wide range of mutations in the type II receptor for bone morphogenetic protein (BMPR-II) have been shown to underlie primary pulmonary hypertension. To determine the mechanism of altered BMPR-II function, we employed transient transfection studies in cell lines and primary cultures of pulmonary vascular smooth muscle cells using green fluorescent protein (GFP)-tagged wild-type and mutant BMPR2 constructs and confocal microscopy to localize receptors. Substitution of cysteine residues in the ligand binding or kinase domain prevented trafficking of BMPR-II to the cell surface, and reduced binding of (125)I-BMP4. In addition, transfection of cysteine-substituted BMPR-II markedly reduced basal and BMP4-stimulated transcriptional activity of a BMP/Smad responsive luciferase reporter gene (3GC2wt-Lux), compared with wild-type BMPR-II, suggesting a dominant-negative effect of these mutants on Smad signalling. In contrast, BMPR-II containing non-cysteine substitutions in the kinase domain were localized to the cell membrane, although these also suppressed the activity of 3GC2wt-Lux. Interestingly, BMPR-II mutations within the cytoplasmic tail trafficked to the cell surface, but retained the ability to activate 3GC2wt-Lux. Transfection of mutant, but not wild-type, constructs into a mouse epithelial cell line (NMuMG cells) led to activation of p38(MAPK) and increased serum-induced proliferation compared with the wild-type receptor, which was partly p38(MAPK)-dependent. We conclude that mutations in BMPR-II heterogeneously inhibit BMP/Smad-mediated signalling by diverse molecular mechanisms. However, all mutants studied demonstrate a gain of function involving upregulation of p38(MAPK)-dependent proproliferative pathways.

Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Publishing Authors By Initials

N Rudarakanchana,JA Flanagan,H Chen,PD Upton,R Machado,D Patel,RC Trembath,NW Morrell,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-serine-threonine kinases: mitogen-activated protein kinases: p38 mitogen-activated protein kinases research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-serine-threonine kinases: mitogen-activated protein kinases: p38 mitogen-activated protein kinases research

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Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Human molecular genetics

VOLUME: 11

Page Numbers: 1517-25

Journal Abbreviation: Hum. Mol. Genet.

ISSN: 0964-6906

DAY: 15

MONTH: Jun

YEAR: 2002

Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Information

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LANGUAGE: eng

NlmUniqueID: 9208958

Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Keywords Mesh Terms:

KEYWORDS: p38 Mitogen-Activated Protein Kinases

MESH TERMS: metabolism

Chemical & Substance for Abstract: Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Information

Substance Name: Protein-Serine-Threonine Kinases

Registry Number: EC 2.7.11.1

Grant and Affiliation Information for Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension.

AFFILIATION: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, UK.

Country: England

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MEDLINETA: Hum Mol Genet

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