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J. Biol. Chem., Vol. 276, Issue 29, 27709-27715, July 20, 2001
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From the Activation of signal transducer and activator of
transcription 3 (STAT3) by interleukin-6 (IL-6) involves
phosphorylation of Tyr-705 and Ser-727, both of which are critical for
STAT3 transactivation. Here, we demonstrate that IL-6 activates Rac-1
and SEK-1/MKK-4 of the stress-activated protein kinase
pathway, as well as protein kinase C
Sequential Activation of Rac-1, SEK-1/MKK-4, and Protein Kinase
C
Is Required for Interleukin-6-induced STAT3 Ser-727
Phosphorylation and Transactivation*
§,§, and
Department of Genetics, Biological
Center, Kerklaan 30, 9751 NN Haren, The Netherlands, the
§ Department of Hematology, University Hospital Groningen,
9700 RB Groningen, The Netherlands, and the ¶ University
College London, Department of Medicine, The Rayne Institute, 5 University St., London WC1E 6JJ, United Kingdom
(PKC), as indicated
by PKC Thr-505 phosphorylation. However, JNK-1, the end point kinase
of the stress-activated protein kinase pathway signal transduction
cascade, is not activated by IL-6. PKC was found to be associated
with SEK-1/MKK-4 in unstimulated HepG2 cells but rapidly dissociates
from SEK-1/MKK-4 upon IL-6 stimulation to become associated with STAT3.
Inhibition of PKC using rottlerin (6 µM) or by
overexpression of dominant negative PKC demonstrates that PKC
kinase activity is required for STAT3 Ser-727 phosphorylation and
transactivation but not for STAT3 Tyr-705 phosphorylation or nuclear
import. PKC signals downstream of Rac-1 and SEK-1/MKK-4, because
enhanced STAT3 transactivation induced by overexpression of
constitutive active RacV12 was strongly abrogated by rottlerin, whereas
IL-6-induced SEK-1/MKK-4 Thr-223 phosphorylation was not affected under
these conditions. Studying the kinetics of STAT3 and PKC
phosphorylation in cytoplasmic and nuclear fractions revealed that
STAT3 Tyr-705 phosphorylation and nuclear translocation precedes PKC
Thr-505 and STAT3 Ser-727 phosphorylation. Furthermore, the
IL-6-induced PKC Thr-505 and STAT3 Ser-727 phosphorylation were only
observed in nuclear fractions of HepG2 cells. These results demonstrate
that IL-6-induced STAT3 transactivation involves the sequential
activation of Rac-1 and SEK-1/MKK-4, which leads to nuclear
translocation of PKC by release from a SEK-1/MKK-4-containing
complex. Our results further indicate that PKC-mediated STAT3
Ser-727 phosphorylation is mainly a nuclear event.
*
This work was supported by Grants RUG 96-1217 and RUG
00-2316 from the Dutch Cancer Foundation.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. Tel.: 050-3632092;
Fax: 050-3632348; E-mail: W.Kruijer@biol.rug.nl.
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