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Vol. 12, Issue 10, 3282-3294, October 2001
Instituto de Investigaciones Biomédicas, CSIC, Madrid,
Spain
Stats (signal transducers and activators of transcription) are
latent cytoplasmic transcription factors that on a specific stimulus
migrate to the nucleus and exert their transcriptional activity. Here
we report a novel signaling pathway whereby RhoA can efficiently
modulate Stat3 transcriptional activity by inducing its simultaneous
tyrosine and serine phosphorylation. Tyrosine phosphorylation is
exerted via a member of the Src family of kinases (SrcFK) and JAK2,
whereas the JNK pathway mediates serine phosphorylation. Furthermore,
cooperation of both tyrosine as well as serine phosphorylation is
necessary for full activation of Stat3. Induction of Stat3 activity
depends on the effector domain of RhoA and correlates with induction of
both Src Kinase-related and JNK activities. Activation of Stat3 has
biological implications. Coexpression of an oncogenic version of RhoA
along with the wild-type, nontransforming Stat3 gene,
significantly enhances its oncogenic activity on human HEK cells,
suggesting that Stat3 is an essential component of RhoA-mediated
transformation. In keeping with this, dominant negative Stat3 mutants
or inhibition of its tyrosine or serine phosphorylation completely
abrogate RhoA oncogenic potential. Taken together, these results
indicate that Stat3 is an important player in RhoA-mediated oncogenic
transformation, which requires simultaneous phosphorylation at both
tyrosine and serine residues by specific signaling events triggered by
RhoA effectors.
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