D. Anhuf et al., Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M:Structural receptor requirements for signal attenuation, J IMMUNOL, 165(5), 2000, pp. 2535-2543
Stimulation of the IL-6R complex leads to Src homology domain containing ty
rosine phosphatase 2 (SHP2) recruitment to the receptor subunit gp130 and i
ts subsequent tyrosine phosphorylation. SHP2 is a two-SH2 domain-containing
protein tyrosine phosphatase that is activated by many cytokines and growt
h factors. SHP2 counteracts the activation of transcription factors of the
STAT family and the induction of IL-6-responsive genes. Tyrosine 759 of gp1
30, the signal transducing subunit of the IL-6R complex, is essential for t
he phosphorylation of SHP2. Mutation of tyrosine 759 to phenylalanine leads
to an enhanced inducibility of IL-6-dependent genes. Here we demonstrate t
hat no further tyrosines in the cytoplasmic part of gp130 are required for
the phosphorylation of SHP2. We also tested whether the tyrosine 759 motifs
in both subunits of the gp130 dimer are required for SHP2 association and
tyrosine phosphorylation. Interestingly, one SHP2-recruiting phosphotyrosin
e motif in a single chain of the gp130 dimer is sufficient to mediate SHP2
association to the gp130 receptor subunit and its tyrosine phosphorylation
as well as to attenuate IL-6-dependent gene induction. Furthermore, we show
that repression of gene induction via Y759 does not require the presence o
f the SHP2 and STAT recruitment sites within the same receptor subunit, but
within the same receptor complex. The Y759 motif in gp130 also attenuates
gene induction mediated by the oncostatin M and leukemia inhibitory factor
receptor complexes, which both contain gp130 as the shared subunit.