Editors' ChoiceInflammation

EGFR and IL-6R Cooperate

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Science Signaling  29 Oct 2013:
Vol. 6, Issue 299, pp. ec262
DOI: 10.1126/scisignal.2004829

Binding of the proinflammatory cytokine interleukin-6 (IL-6) to its receptor (IL-6R) results in the phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3), which forms homodimers that translocate to the nucleus to stimulate the expression of IL-6 target genes. Soon after activation, IL-6R signaling is normally inhibited in a STAT3-dependent feedback mechanism by the action of suppressor of cytokine signaling 3 (SOCS3), which interacts with IL-6R. However, even when SOCS3 is present, a second wave of IL-6–dependent STAT3 phosphorylation occurs through a mechanism that is unclear. Sustained STAT3 activation is associated with various cancers and inflammatory diseases. Wang et al. confirmed previous findings by showing that IL-6–dependent STAT3 phosphorylation occurred in a biphasic manner in experiments in which a human colon cancer cell line (DLD1 cells) was treated with IL-6 that was then removed by washing; the second wave of STAT3 phosphorylation occurred 4 hours after the removal of IL-6. A blocking antibody against IL-6 inhibited the second wave of STAT3 phosphorylation, suggesting that secreted IL-6 acted in an autocrine manner to activate STAT3. Noting previous studies that showed that the epidermal growth factor receptor (EGFR) phosphorylates STAT3 in an IL-6–dependent manner, the authors treated cells with the EGFR inhibitor erlotinib and found that it blocked the second, but not the first, wave of STAT3 phosphorylation in response to IL-6. Knockdown of EGFR in DLD1 cells reduced the extent of the second wave of STAT3 phosphorylation compared with that in control cells, and expression of a mutant EGFR that lacks a docking site for STAT3 in human embryonic kidney (HEK) 293 cells inhibited the second wave of STAT3 phosphorylation. EGFR coimmunoprecipitated with STAT3 and IL-6R in DLD1 cells, and these interactions were increased in response to IL-6 at times that coincided with the second wave of STAT3 phosphorylation. Finally, gene expression analysis of IL-6–stimulated DLD1 cells in which EGFR was knocked down or that were treated with an antibody that blocks IL-6R activation after IL-6 washout identified a subset of IL-6 target genes that were expressed only during the second wave of STAT3 activation. These genes produce proteins that are mediators of inflammation or are associated with cancer. Together, these data suggest that EGFR enables sustained IL-6–dependent STAT3 activation that may have implications for cancers and inflammatory diseases.

Y. Wang, A. H. H. van Boxel-Dezaire, H. Cheon, J. Yang, G. R. Stark, STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc. Natl. Acad. Sci. U.S.A. 110, 16975–16980 (2013). [Abstract] [Full Text]

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