Schematic structure of gp130. Binding of IL-6 to IL-6R induces homodimerization of gp130, activating JAK associating with gp130 at Box1. This is followed by the tyrosine phosphorylation of the distal part of gp130 and recruitment of STAT3. STAT3 is then tyrosine-phosphorylated by JAK. SHP-2 on the second tyrosine (Y2) residue of gp130 activates the MAP kinase pathway. JAK, Janus family tyrosine kinase; SHP-2, Src homology protein 2 tyrosine phosphatase-2; STAT, signal transducer and activator of transcription; Y(2,3, etc.), (second, third, etc.) tyrosine residue (from the membrane).