Model for Stat3 signaling. Stat3 is a transcription factor, which is activated in response to many cytokines and growth factors that bind to specific receptors. Upon ligand-receptor binding, Stat3 is recruited to the plasma membrane, where it becomes activated via phosphorylation of a tyrosine residue either directly by RTKs, such as the PDGF receptor and EGF receptor, or by non-RTKs, such as Src and JAK. Stat3 activation induces dimerization via reciprocal phosphotyrosine–SH2 interaction between two Stat3 molecules. The Stat3 dimers then translocate to the nucleus where they bind to consensus sequences on the promoter of target genes and activate their transcription. Stat3 activation is tightly regulated by different negative regulators of phosphorylation, such as phosphatases, suppressor of cytokine signaling, and protein inhibitor of activated Stats. In many cancer-derived cell lines and primary tumors Stat3 is constitutively activated either as a consequence of deregulated signaling from positive effectors (e.g., overexpression of growth factor receptors and their ligands) or by abnormal activity of negative effectors. SOCS, suppressor of cytokine signaling; PIAS, protein inhibitor of activated Stats.