Downhill to tumor growth

The Ski family of nuclear oncoproteins (for Sloan Kettering Institute, where they were identified in the early 1980s) is known to trigger tumor growth through repression of TGF-β signaling. Ski inhibits this pathway via interactions with Smad proteins, but the molecular mechanisms involved have been unclear. In November 1 Cell, Jia-Wei Wu and colleagues at Princeton University, New Jersey, USA, describe the crystal structure of Ski, explaining the mechanism of Ski-mediated repression of TGF-β signaling (Cell, 111:357–367, November 1, 2002).

Wu et al. determined the crystal structure of a complex between a conserved Smad4 binding fragment of Ski and the MH2 domain of Smad4 at 2.85Å. They observed that the Ski binding surface on Smad4 significantly overlaps with that required for binding of the R-Smads. Ski thus disrupts the formation of a functional complex between the Co- and R-Smads, explaining how it could lead to...