Regulation of intracellular Stat3 signalling. Stat3 signalling is induced by various kinases (green) in a phosphorylation dependent manner (green arrows), and counteracted by several regulatory proteins (red). For instance, Stat3 activation occurs in response to gp130 homodimerization following binding of IL6 or IL11 (blue) to their specific transmembrane receptor α-subunits (white) . Phosphorylation of four membrane distal tyrosine (Y, black) residues by constitutively associated JAK-family tyrosine kinases (TK) is sufficient to enable src-homology domain (SH)-2 mediated binding of STAT3 and, to a lesser extent, of STAT1. Once tyrosine phosphorylated, STAT1/3 form homo- and heterodimers, which translocate and trans-activate target genes, including the negative regulator SOCS3. STAT3 can also be phosphorylated by certain cytosolic TKs and receptor TK. Meanwhile, serine threonine kinases (STK) mediate serine-phosphorylation that maximizes the transcriptional activity of STAT3 and enables its mitochondrial targeting. Gp130 also engages the Ras/ERK pathway through binding of the tyrosine phosphatase SHP2 to the membrane proximal phospho-YxxV consensus sequence (red, where V is valine and × any amino acid). This phosphor-tyrosine also provides the binding site for SOCS3 to mediate proteasomal degradation of ligand-occupied receptor complexes. Gp130 signaling is also attenuated by the Y-phosphatase activity of SHP2, while cytoplasmic PIAS3 protein sequesters Y-phosphorylated STAT3 from homodimerization, nuclear translocation and target gene activation. Representative examples of different types of bona-fide Stat3 target genes are listed .