Transmembrane signaling of IL-6, which is a major growth factor for MM. Binding of IL-6 to the α chain (gp80) of the IL-6 receptor (IL-6R) causes the formation of multimeric complexes composed of 2 IL-6R α chains, 2 β chains (IL-6Rβ or gp130), and 2 IL-6 molecules. Subsequently, tyrosine kinases (JAKs and Src kinases, in particular Hck) which are bound constitutively to the IL-6Rβ, become activated and (trans)phosphorylate the receptor. This creates specific docking sites for several signaling proteins including STAT1, STAT3, and Shc (?) on the IL-6Rβ, allowing further phosphorylation of these proteins by receptor-associated kinases. Activation of Shc recruits Grb2/Sos1 to the cell membrane. Sos1, a Ras-GDP/GTP exchange factor activates Ras; this activates a signaling cascade of several serine/threonine kinases including Raf-1, MKK, MAPK. Finally, MAPK phosphorylates substrates like c-Myc, c-Jun, c-Fos, RSK, and these events eventually enhance MM proliferation or prevent apoptosis. Upon phosphorylation, STAT1 and STAT3 form homodimers and heterodimers that are translocated to the nucleus and act as transcription factors for IL-6–induced promoters. Although the Ras-MAPK signaling cascade is believed to promote MM growth, no such function has yet been reported for the JAK-STAT pathway, believed to trigger rather metabolic events.