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Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK)
1Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore.
Abstract:
STAT proteins are activated by phosphorylation at specific tyrosine residue at the carboxy-terminus which is required for dimer-formation, nuclear translocation, DNA binding and transcriptional activity in cells treated with cytokines and growth factors. Recent studies have indicated that STATs are also phosphorylated by MAPK, or extracellular signal-regulated kinase (ERK) on serine. We investigated the role of ERK on the regulation of STAT activity. Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2. To unravel the mechanism of repression, we further showed that Stat3 DNA binding activity and its tyrosine phosphorylation are also inhibited under the same conditions. ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment. We also detected an association of ERK2 and Stat3 in vivo which is modulated positively by activation of ERK2, but negatively by Jak2. We propose that MAP kinase cascade may negatively regulate Stat3 activities by decreasing its tyrosine phosphorylation and also possibly by association.
Insights
Extracellular signal-regulated kinase (ERK) activation by MEK1 represses Signal transducer and activator of transcription 3 (STAT3) activity. ERK2 phosphorylates STAT3 on serine, decreasing its tyrosine phosphorylation and DNA binding, thus inhibiting STAT3 transcriptional activity.
Area of Science:
- Molecular Biology
- Cell Signaling
- Signal Transduction
Background:
- Signal transducer and activator of transcription (STAT) proteins are crucial transcription factors activated by tyrosine phosphorylation.
- STAT activity is essential for cellular responses to cytokines and growth factors.
- Recent findings suggest STATs can also be phosphorylated on serine by mitogen-activated protein kinases (MAPKs), specifically extracellular signal-regulated kinase (ERK).
Purpose of the Study:
- To investigate the regulatory role of ERK in STAT activity.
- To elucidate the molecular mechanisms by which ERK influences STAT3 function.
Main Methods:
- Investigated the effect of ERK2, activated by MEK1, on STAT3 transcriptional activity.
- Assessed STAT3 DNA binding and tyrosine phosphorylation under ERK activation.
- Examined ERK2-STAT3 interactions in vivo.
- Analyzed STAT3 serine phosphorylation by ERK2.
Main Results:
- ERK2 activation by MEK1 represses STAT3 transcriptional activity induced by Src or Jak-2.
- ERK2 inhibits STAT3 DNA binding and tyrosine phosphorylation.
- ERK2 phosphorylates STAT3 on three serine residues, reducing EGF-induced tyrosine phosphorylation.
- An in vivo association between ERK2 and STAT3 was observed, modulated by ERK2 and Jak2 activation.
Conclusions:
- The MAP kinase cascade, specifically ERK, negatively regulates STAT3 activity.
- ERK-mediated repression of STAT3 involves decreased tyrosine phosphorylation and potential direct association.
- This provides a novel mechanism for crosstalk between MAPK and STAT signaling pathways.