Skip to main content

Signal integration and gene induction by a functionally distinct STAT3 phosphoform.

Publication ,  Journal Article
Waitkus, MS; Chandrasekharan, UM; Willard, B; Tee, TL; Hsieh, JK; Przybycin, CG; Rini, BI; Dicorleto, PE
Published in: Mol Cell Biol
May 2014

Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr(705) phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr(714) and Ser(727) by glycogen synthase kinase 3α and -β (GSK-3α/β). Both Thr(714) and Ser(727) are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/β is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr(705)-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/β-STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/β-STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

May 2014

Volume

34

Issue

10

Start / End Page

1800 / 1811

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptor, PAR-1
  • Protein Processing, Post-Translational
  • Protein Binding
  • Promoter Regions, Genetic
  • Phosphorylation
  • Kidney Neoplasms
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Waitkus, M. S., Chandrasekharan, U. M., Willard, B., Tee, T. L., Hsieh, J. K., Przybycin, C. G., … Dicorleto, P. E. (2014). Signal integration and gene induction by a functionally distinct STAT3 phosphoform. Mol Cell Biol, 34(10), 1800–1811. https://doi.org/10.1128/MCB.00034-14
Waitkus, Matthew S., Unni M. Chandrasekharan, Belinda Willard, Thomas L. Tee, Jason K. Hsieh, Christopher G. Przybycin, Brian I. Rini, and Paul E. Dicorleto. “Signal integration and gene induction by a functionally distinct STAT3 phosphoform.Mol Cell Biol 34, no. 10 (May 2014): 1800–1811. https://doi.org/10.1128/MCB.00034-14.
Waitkus MS, Chandrasekharan UM, Willard B, Tee TL, Hsieh JK, Przybycin CG, et al. Signal integration and gene induction by a functionally distinct STAT3 phosphoform. Mol Cell Biol. 2014 May;34(10):1800–11.
Waitkus, Matthew S., et al. “Signal integration and gene induction by a functionally distinct STAT3 phosphoform.Mol Cell Biol, vol. 34, no. 10, May 2014, pp. 1800–11. Pubmed, doi:10.1128/MCB.00034-14.
Waitkus MS, Chandrasekharan UM, Willard B, Tee TL, Hsieh JK, Przybycin CG, Rini BI, Dicorleto PE. Signal integration and gene induction by a functionally distinct STAT3 phosphoform. Mol Cell Biol. 2014 May;34(10):1800–1811.

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

May 2014

Volume

34

Issue

10

Start / End Page

1800 / 1811

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptor, PAR-1
  • Protein Processing, Post-Translational
  • Protein Binding
  • Promoter Regions, Genetic
  • Phosphorylation
  • Kidney Neoplasms
  • Humans