Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants

Biochemistry
Forrester J LiddleDavid A Frank

Abstract

Aberrant activation of STAT transcription factors has been implicated in a variety of cancers. Constitutively active forms of STAT1 and STAT3 (STAT1C and STAT3C) have been developed to determine the effects of STAT activation in isolation from other cytokine-stimulated signaling pathways. These mutants were created by engineering cysteine residues into the carboxy terminus of each STAT molecule, allowing a hypothesized disulfide bond to form between two unphosphorylated monomers. To determine whether the presence of cysteine residues is sufficient to allow for functional activation in the absence of tyrosine phosphorylation, we developed STAT1C and STAT3C mutants that are unable to be phosphorylated on the critical tyrosine residue. Without the tyrosine residue, cysteine containing constitutive STAT mutants failed to transactivate STAT target genes. Furthermore, transfection of STAT dominant negative mutants prevented the activation of STAT1C and STAT3C. Cytokine-induced activation of STAT1C and STAT3C was dramatically prolonged when compared to wild-type proteins and led to extended STAT-dependent gene activation. These data show that tyrosine phosphorylation is required for activation of STAT1C and STAT3C. Additionally, these...Continue Reading

References

Mar 9, 2005·Proceedings of the National Academy of Sciences of the United States of America·Minghao ZhongJames E Darnell

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Citations

Jan 14, 2011·ACS Chemical Biology·Ralf BuettnerJohn C Williams
Jan 12, 2007·Molecular BioSystems·Cheh Peng Lim, Xinmin Cao
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Jan 17, 2008·Journal of Cell Science·Pavel KrejciWilliam R Wilcox
Jul 3, 2021·Pharmaceuticals·Sara VerduraJavier A Menendez

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