Bone morphogenetic protein-2 inhibits MAPK-dependent Elk-1 transactivationand DNA synthesis induced by EGF in mesangial cells

Bone morphogenetic protein-2 (BMP-2) is a member of the TGF beta superfamil y of growth and differentiation factors. We investigated the effect of BMP- 2 on epidermal growth factor (EGF)-induced mitogenic signaling in kidney gl omerular mesangial cells. BMP-2 dose-dependently inhibits EGF-induced DNA s ynthesis. Maximum effect was obtained at a concentration of 100 ng/ml. BMP- 2 had no inhibitory effect on the EGF receptor (EGFR)-associated tyrosine k inase activity indicating that inhibition of DNA synthesis is due to regula tion of post-receptor signaling event(s). EGF stimulates MAPK activity in m esangial cells in a time-dependent manner. Inhibition of MAPK by the MEK in hibitor PD098059 blocks EGF-induced DNA synthesis indicating the requiremen t of this enzyme activity in EGF-mediated mitogenic signaling. Furthermore, we show that exposure of mesangial cells to BMP-S blocks EGF-induced MAPK activity which leads to phosphorylattion of Elk-1 transcription factor. Usi ng a GAL-4 DNA binding-domain-Elk-1 transactivation domain fusion protein-b ased reporter assay, we demonstrate that BMP-2 inhibits EGF-induced Elk-1-m ediated transcription. These data provide the first evidence that BMP-2 sig naling in mesangial cells initiates a negative regulatory cross-talk with M APK-based transcription to inhibit EGF-induced DNA synthesis. (C) 1999 Acad emic Press.