Stat1 is an inhibitor of Ras-MAPK signaling and Rho small GTPase expression with implications in the transcriptional signature of Ras transformed cells

The signal transducer and activator of transcription Stat1 plays an indispensable role in the regulation of innate immunity and tumor immuno-surveillance. The anti-tumor activity of Stat1 is largely dependent on its ability to function downstream of interferon (IFN) signaling. However, anti-tumor functions of Stat1 that are independent of IFN signaling have started to emerge. For example, we recently reported that the anti-tumor activity of Stat1 in Ras transformation is affected by Stat1 phosphorylation at tyrosine (Y) 701 and serine (S) 727, both of which determine p27(Kip1) expression and function (PLoS ONE 2008; 3: 3476). Herein, we provide further evidence that these site-specific phosphorylation events of Stat1 regulate the inhibition of the Ras-MAPK pathway and expression of RhoA, Cdc42 and Rac1 GTPases in Ras transformed cells. Site-specific Stat1 phosphorylation also controls the transcriptional activities of Stat3 and Stat5 and is capable of orchestrating a complex regulatory network that influences the expression of genes involved in cell cycle control, cell-cell adhesion and signal transduction. These findings further substantiate the notion that Stat1 is as a master regulator of Ras-mediated transformation, a property that is intimately affected by its phosphorylation at Y701 and S727.