Integration of BMP and Wnt signaling via vertebrate Smad1/5/8 and Drosophila Mad.

BMPs pattern the dorsal-ventral axis of vertebrate embryos. Smad1/5/8 transduces the BMP signal, and receives phosphorylation inputs from both MAPK and GSK3. Phosphorylation of Smad1 by MAPK and GSK3 result in its polyubiquitination and transport to the centrosome where it is degraded by the proteasome. These linker phosphorylations inhibit BMP/Smad1signaling by shortening its duration. Wnt, which negatively regulates GSK3 activity, prolongs the BMP/Smad1 signal. Remarkably, linker-phosphorylated Smad1 has been shown to be inherited asymmetrically during cell division. Drosophila contains a single Smad1/5/8 homologue, Mad, and is stabilized by phosphorylation-resistant mutations at GSK3 sites, causing Wingless-like effects. We summarize here the significance of linker-phosphorylated Smad1/Mad in relation to signal intensity and duration, and how this integrates the Wnt and BMP pathways during cell differentiation.