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Figure 5 Consequences of bone morphogenetic protein type-II receptor (BMPR2) mutations on signaling. Mutation analysis demonstrated that some BMPR2 mutations occur within exon 1 of the gene and would be predicted to cause nonsense-mediated messenger ribonucleic acid decay and failure to express the mutant protein, resulting in haploinsufficiency. Although this finding may be true for some mutations, it was also found in transfected cells that mutations involving the ligand binding or kinase domain of BMPR-II could exert a dominant negative effect on BMPR-II signaling via the Smad pathway. The mechanism by which BMPR-II mutants disrupt BMP/Smad signaling is heterogeneous, and mutation specific. Thus, substitution of cysteine residues within the ligand binding or kinase domain of BMPR-II leads to failure of trafficking of the mutant protein to the cell surface, which may interfere with wild-type receptor trafficking. In contrast, noncysteine mutations within the kinase domain reach the cell surface but fail to activate a Smad-responsive luciferase reporter gene. Interestingly, BMPR-II mutants with missense mutations involving the cytoplasmic tail reached the cell surface but were still capable of activating the Smad-responsive luciferase reporter gene. However, a feature common to all mutants transfected into normal mouse epithelial cells was ligand-independent activation of p38^MAPK and enhanced serum-induced proliferation. Based on the results of these studies it was hypothesized that reduced cell-surface expression of BMPR-II favors activation of p38^MAPK-dependent pro-proliferative pathways, while inhibiting Smad-dependent signaling in a mutation-specific manner. Thus, a feature common to all mutants is a gain of function involving p38^MAPK activation.