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Identification of Functional Protein Regions Through Chimeric Protein Construction
11:39

Identification of Functional Protein Regions Through Chimeric Protein Construction

Published on: January 8, 2019

Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for

D Anhuf1, M Weissenbach, J Schmitz

  • 1Department of Biochemistry, Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany.

Journal of Immunology (Baltimore, Md. : 1950)
|August 18, 2000
PubMed

Insights

Interleukin-6 receptor (IL-6R) complex stimulation recruits and phosphorylates SHP2 phosphatase. A single Y759 motif in gp130 is sufficient for SHP2 binding and IL-6 gene induction attenuation.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Immunology

Background:

  • The Interleukin-6 receptor (IL-6R) complex is crucial for cellular responses mediated by IL-6.
  • Stimulation of the IL-6R complex involves the recruitment and phosphorylation of Src homology domain containing tyrosine phosphatase 2 (SHP2) to the gp130 receptor subunit.
  • SHP2 plays a role in counteracting STAT transcription factors and IL-6-responsive gene induction.

Purpose of the Study:

  • To investigate the role of tyrosine 759 (Y759) of gp130 in SHP2 recruitment and phosphorylation.
  • To determine if other tyrosines in gp130 are necessary for SHP2 phosphorylation.
  • To elucidate the requirement of Y759 motifs in gp130 dimers for SHP2 association and IL-6 signaling attenuation.

Main Methods:

  • Site-directed mutagenesis of gp130 tyrosine residues.
  • Analysis of SHP2 recruitment and tyrosine phosphorylation.
  • Assessment of IL-6-dependent gene induction.
  • Investigation of receptor complex stoichiometry.

Main Results:

  • Mutation of Y759 to phenylalanine enhances IL-6-dependent gene induction, highlighting Y759's inhibitory role.
  • No other tyrosines in the cytoplasmic domain of gp130 are essential for SHP2 phosphorylation.
  • A single Y759 phosphotyrosine motif in one gp130 chain is sufficient for SHP2 binding, phosphorylation, and attenuation of IL-6-induced gene expression.
  • Repression of gene induction by Y759 does not require SHP2 and STAT recruitment sites on the same subunit, but within the same receptor complex.
  • The Y759 motif in gp130 also attenuates gene induction mediated by related receptor complexes (Oncostatin M and Leukemia Inhibitory Factor).

Conclusions:

  • Tyrosine 759 of gp130 is a critical site for SHP2 recruitment and phosphorylation, negatively regulating IL-6 signaling.
  • The presence of a single Y759 motif within the gp130 dimer is sufficient to mediate SHP2-dependent attenuation of IL-6-induced gene expression.
  • This regulatory mechanism involving Y759 and SHP2 is conserved across related cytokine receptor complexes sharing the gp130 subunit.

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