SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130

Ute Lehmann, Jochen Schmitz, Manuela Weissenbach, Radoslaw M. Sobota, Michael Hörtner, Kerstin Friederichs, Iris Behrmann, William Tsiaris, Atsuo Sasaki, Jens Schneider-Mergener, Akihiko Yoshimura, Benjamin G. Neel, Peter C. Heinrich, Fred Schaper

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Abstract

Interleukin-6 (IL-6) activates the Jak/STAT pathway as well as the mitogen-activated protein kinase cascade. Tyrosine 759 of the IL-6 signal-transducing receptor subunit gp130 has been identified as being involved in negative regulation of IL-6-induced gene induction and activation of the Jak/STAT pathway. Because this site is known to be a recruitment motif for the protein-tyrosine phosphatase SHP2, it has been suggested that SHP2 is the mediator of tyrosine 759-dependent signal attenuation. We recently observed that the suppressor of cytokine-signaling SOCS3 also acts through the tyrosine motif 759 of gp130. However, the relative contributions of SHP2 and SOCS3 to the repression of IL-6 signaling are not understood. Therefore, we designed experiments allowing the independent recruitment of each of these proteins to the IL-6-receptor complex. We show that receptor- and membrane-targeted SHP2 counteracts IL-6 signaling independent of SOCS3 binding to gp130. On the other hand, SOCS3 inhibits signaling in cells expressing a truncated SHP2 protein, which is not recruited to gp130. These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130.

Original languageEnglish
Pages (from-to)661-671
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number1
DOIs
Publication statusPublished - 2003 Jan 3
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lehmann, U., Schmitz, J., Weissenbach, M., Sobota, R. M., Hörtner, M., Friederichs, K., Behrmann, I., Tsiaris, W., Sasaki, A., Schneider-Mergener, J., Yoshimura, A., Neel, B. G., Heinrich, P. C., & Schaper, F. (2003). SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. Journal of Biological Chemistry, 278(1), 661-671. https://doi.org/10.1074/jbc.M210552200