Potential Roles of Stat1 and Stat3 in Cellular Transformation

The STAT proteins are latent cytoplasmic transcriptionfactors that become tyrosine-phosphorylated by a varietyof intracellular kinases, most often in response to cytokines and growth factors (Schindler and Darnell 1995;Darnell 1997). Receptors with intrinsic tyrosine kinases(RTKs) may phosphorylate Stats directly or possibly actthrough other associated kinases of the nonreceptor tyrosine kinase (NRTK) family such as src (Cao et al. 1996;Campbell et al. 1997; Olayioye et al. 1999; Vignais andGilman 1999). Cytokine receptors, in general, have Januskinases (Jaks) associated noncovalently, which after ligand-dependent trans-activation catalyze phosphate addition to tyrosine residues on the internal domains of cytokine receptors. These receptor tyrosine phosphates actas docking sites for the –SH2-containing Stats. Proximityto the activated Jaks then leads to tyrosine phosphorylation on Stats followed by SH2-phosphotyrosine-mediateddimerization, nuclear accumulation of the dimers, andparticipation in transcriptional activation...