Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells

The bone morphogenic proteins (BMPs) play important roles in vertebrate dev elopment. In Xenopus, BMPs act as epidermal inducers and also as negative r egulators of neurogenesis. Antagonism of BMP signaling results in neuraliza tion. BMPs signal through the cell-surface receptors and downstream Smad mo lecules. Upon stimulation with BMP, Smad1, Smad5. and Smad8 are phosphoryla ted by the activated BMP receptors, form a complex with Smad4, and transloc ate into the nucleus, where they regulate the expression of BMP target gene s. Here, we show that the Ski oncoprotein can block BMP signaling and the e xpression of BMP-responsive genes in both Xenopus and mammalian cells by di rectly interacting with and repressing the activity of BMP-specific Smad co mplexes. This ability to antagonize BMP signaling results in neuralization by Ski in the Xenopus embryo and blocking of osteoblast differentiation of murine W-20-17 cells. Thus, Ski is able to repress the activity of all rece ptor-associated Smads and may regulate vertebrate development by modulating the signaling activity of transforming growth factor-beta family members.