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.
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 formulation 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.
Neumann
C
C
Medizinische Klinik, Klinikum Innenstadt, Universität, München, Germany.
Zehentmaier
G
G
Danhauser-Riedl
S
S
Emmerich
B
B
Hallek
M
M
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004790:Enzyme Induction / Q000276:immunology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D008875:Middle Aged; D009101:Multiple Myeloma / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000276:immunology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D066246:ErbB Receptors; D051380:GRB2 Adaptor Protein; D015850:Interleukin-6; D046911:Macromolecular Substances; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C495948:GRB2 protein, human; C528024:SHC1 protein, human; C064740:epidermal growth factor receptor-neu receptor; C501009:HRAS protein, human