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J Biol Chem, Vol. 275, Issue 17, 12848-12856, April 28, 2000
From the Institut für Biochemie, Rheinisch-Westfälische
Technische Hochschule Aachen, Pauwelsstra Interleukin-6 is involved in the regulation of
many biological activities such as gene expression, cell proliferation,
and differentiation. The control of the termination of cytokine
signaling is as important as the regulation of initiation of signal
transduction pathways. Three families of proteins involved in the
down-regulation of cytokine signaling have been described recently: (i)
SH2 domain-containing protein-tyrosine phosphatases (SHP),
(ii) suppressors of cytokine signaling (SOCS), and (iii) protein
inhibitors of activated STATs (PIAS). We have analyzed the interplay of
two inhibitors in the signal transduction pathway of interleukin-6 and
demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act
independently but are functionally linked. The activation of one
inhibitor modulates the activity of the other; Inhibition of SHP2
activation leads to increased SOCS3-mRNA levels, whereas increased
expression of SOCS3 results in a reduction of SHP2 phosphorylation
after activation of the interleukin-6 signal transduction pathway.
Furthermore, we show that tyrosine 759 in gp130 is essential for both
SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our
results suggest differences in the function of SOCS1 and SOCS3 and a
link between SHP2 and SOCS3.
SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal
Transduction through the SHP2 Recruitment Site of gp130*
, and
e 30, D-52074 Aachen, Germany
*
This work was supported by grants from the Deutsche
Forschungsgemeinschaft (Bonn, Germany) and the Fonds der Chemischen
Industrie (Frankfurt, Germany).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Medical School RWTH
Aachen, Department of Biochemistry, Pauwelsstrae 30, D-52074 Aachen
Germany. Tel.: 0049 241 80 888 30; Fax: 0049 241 88 884 28; E-mail:
heinrich@rwth-aachen.de.
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