Bone morphogenetic proteins (BMPs) play an important role in nephrogenesis. The biologic effect and mechanism of action of these proteins in the adult kidney has not yet been studied. We investigated the effect of BMP2, a member of these growth and differentiation factors, on mitogenic signal transduction pathways induced by platelet-derived growth factor (PDGF) in glomerular mesangial cells. PDGF is a growth and survival factor for these cells in vitro and in vivo. Incubation of mesangial cells with increasing concentrations of BMP2 inhibited PDGF-induced DNA synthesis in a dose-dependent manner with maximum inhibition at 250 ng/ml. Immune complex tyrosine kinase assay of PDGF receptor  immunoprecipitates from lysates of mesangial cells treated with PDGF showed no inhibitory effect of BMP2 on PDGF receptor tyrosine phosphorylation. This indicates that the inhibition of DNA synthesis is likely due to postreceptor events. However, BMP2 significantly inhibited PDGF-stimulated mitogen-activated protein kinase (MAPK) activity that phosphorylates the Elk-1 transcription factor, a component of the ternary complex factor. Using a fusion protein-based reporter assay, we also show that BMP2 blocks PDGF-induced Elk-1-mediated transcription. Furthermore, we demonstrate that BMP2 inhibits PDGF-induced transcription of c-fos gene, a natural target of Elk-1 that normally forms a ternary complex that activates the serum response element of the c-fos gene. These data provide the first evidence that in mesangial cells, BMP2 signaling crosstalks with MAPK-based transcriptional events to inhibit PDGF-induced DNA synthesis. One target for this inhibition is the early response gene c-fos.Bone morphogenetic proteins are a group of growth and differentiation factors that were originally identified by their ability to form ectopic bone (1, 2). Recently several members of this family have been cloned. These proteins contain seven highly conserved cysteines in the C terminus that are characteristic of the TGF- 1 family of proteins and thus fall into that broad superfamily (3-6). BMPs play an important role in the development of many organs, including lung, heart, teeth, gut, skin, and particularly the kidney (4). BMP7, a member of this large family, has been shown to be abundantly expressed in the ureteric bud epithelium before condensation of mesenchyme during nephrogenesis. BMP7 is also expressed during glomerulogenesis (7). BMP7 null mice die after birth because of early cessation of kidney development (8, 9). The rudimentary kidneys at birth lack glomeruli, the filtering units, likely due to lack of differentiation of metanephric mesenchymal cells (8).High affinity binding of BMP2, another member of this family, has been identified in a large variety of tissues and cells, including the kidney (10). Similar to TGF-, BMPs exert their effect via type I and type II transmembrane serine-threonine kinase receptors (4 -6). Binding of BMPs to the receptor induces phosphorylation of the type I receptor in the intracellular GS domain (6). S...
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