Interleukin‐6 induces tyrosine phosphorylation of the Ras activating protein Shc, and its complex formation with Grb2 in the human multiple myeloma cell line LP‐1

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Abstract
Like many other cytokines and growth factors, interleukin‐6 (IL‐6) activates p21ras. However, the precise biochemical mechanisms inducing this activation are unknown. Therefore, we investigated the effects of IL‐6 on some recently identified signaling intermediates, Shc (Src homology and collagen) and Grb2 (growth factor receptor bound protein 2), known to activate p21ras. In the multiple myeloma cell line LP‐1, IL‐6 stimulated the tyrosine phosphorylation of Shc in a time‐ and concentration‐dependent manner. This led to the complex formation of Shc with Grb2, an adaptor protein known to relocate a p21ras‐GDP exchange factor, Sos1 (Son‐of‐sevenless), to the cell membrane. Taken together, these findings suggest that IL‐6 might activate the Ras signaling pathway via tyrosine phosphorylation of Shc and subsequent recruitment of Grb2. Further studies will elucidate which of the IL‐6 receptor associated non‐receptor tyrosine kinases of the Src kinase or Janus kinase family, mediate these effects.