Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension.
Heterozygous germ line mutations in the gene encoding the bone morphogenetic protein (BMP) type II receptor occur in more than 80% of patients with familial pulmonary arterial hypertension. Because inhibitors of DNA binding (Id) genes are major targets of BMP/Smad signaling, we studied the regulation of these transcription factors in pulmonary artery smooth muscle cells harboring mutations in BMP type II receptor and control cells. Mutant cells demonstrated a marked deficiency in BMP4-stimulated Id1 and Id2 gene and protein expression compared with control cells. Mutant cells were deficient in Smad1/5 signaling in response to BMPs but also in extracellular signal-regulated kinase (ERK)1/2 activation. We provide evidence for an important interaction between Smad1/5 and ERK1/2 signaling in the regulation of Id gene expression. Thus, BMP4-induced Id1 expression was negatively regulated by ERK1/2 activation. The mechanism involves ERK1/2-dependent phosphorylation of the Smad1 linker region (serine 206), which limits C-terminal serine 463/465 phosphorylation and inhibits Smad nuclear accumulation. Furthermore, activation of ERK1/2 by platelet-derived growth factor BB also caused Smad1 linker region phosphorylation and inhibited BMP4-induced Id1 gene expression. In contrast, Id2 expression was positively regulated by ERK1/2. Moreover, we show that both BMP type II receptor mutation and Id1 knockdown leads to loss of growth suppression by BMPs. Taken together, these findings indicate an important interaction between ERK1/2 and Smad1/5 in the regulation of Id genes. Platelet-derived growth factor, via ERK1/2, further impairs the deficiency in Smad signaling found in BMP type II receptor mutant cells. The integration of these signals at the level of Id gene expression may contribute to the pathogenesis of familial pulmonary arterial hypertension.
Yang
Jun
J
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, United Kingdom.
Davies
Rachel J
RJ
Southwood
Mark
M
Long
Lu
L
Yang
Xudong
X
Sobolewski
Anastasia
A
Upton
Paul D
PD
Trembath
Richard C
RC
Morrell
Nicholas W
NW
D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D005192:Family Health; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000166:cytology*; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C497453:ID1 protein, human; C497450:ID2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D052006:Bone Morphogenetic Protein Receptors, Type II