Interleukin-6-induced STAT3 transactivation and Ser(727) phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components
Jj. Schuringa et al., Interleukin-6-induced STAT3 transactivation and Ser(727) phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components, BIOCHEM J, 347, 2000, pp. 89-96
In the present study, signal transducer and activator of transcription 3 (S
TAT3) Ser(727) phosphorylation and transactivation was investigated in rela
tion to activation of mitogen-activated protein (MAP) kinase family members
including extracellular-signal-regulated protein kinase (ERK)-1, c-Jun N-t
erminal kinase (JNK)-1 and p38 ('reactivating kinase') in response to inter
leukin (IL)-6 stimulation. Although IL-6 can activate ERK-1 in HepG2 cells.
STAT3 transactivation and Ser(727) phosphorylation were not reduced by usi
ng the MAP kinase/ERK kinase (MEK) inhibitor PD98059 or by overexpression o
f dominant-negative Raf, IL-6 did not activate JNK-1 in HepG2 cells and STA
TS was a poor substrate for JNK-1 activated by anisomycin, excluding a role
for JNK1 in IL-6-induced STAT3 activation. However, SEK-1/MKK-4 [where SEK
-1 stands for stress-activated protein kinase (SAPK)/ERK kinase 1, and MKK-
4 stands for MAP kinase kinase 4] was activated in response to IL-6 and ove
rexpression of dominant-negative SEK-1/MKK-4 (A-L) reduced both IL-6-induce
d STATS Ser(727) phosphorylation as well as STATS transactivation. Subseque
ntly, the SEK-1/MKK-4 upstream components Vav, Rac-1 and MEKK were identifi
ed as components of a signal transduction cascade that leads to STAT3 trans
activation in response to IL-S stimulation. Furthermore, inhibition of p38
kinase activity with the inhibitor SB203580 did not block STATS Ser727 phos
phorylation but rather increased both basal as well as IL-6-induced STATS t
ransactivation, indicating that p38 may act as a negative regulator of IL-6
induced STAT3 transactivation through a presently unknown mechanism. In co
nclusion, these data indicate that IL-6-induced STATS transactivation and S
er727 phosphorylation is independent of ERK-1 or JNK-1 activity, but involv
es a gp130 receptor signalling cascade that includes Vav, Rac-1, MEKK and S
EK-1/MKK-4 as signal transduction components.