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Tyrosine Phosphorylation Is Required for Functional Activation of Disulfide-Containing Constitutively Active STAT Mutants†

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Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, and Department of Genetics, Biology, and Biochemistry, University of Turin, Via Santena 5 bis, Torino, Italy 10126
Cite this: Biochemistry 2006, 45, 17, 5599–5605
Publication Date (Web):April 6, 2006
https://doi.org/10.1021/bi0525674
Copyright © 2006 American Chemical Society
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    Abstract

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    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 findings suggest the existence of basal phosphorylation that is a dynamic process that involves both phosphorylation and dephosphorylation. The constitutive STAT mutants likely show heightened activity because of the cysteine residues stabilizing these dimers and preventing dephosphorylation, resulting in the accumulation of trancriptionally active STAT dimer complexes.

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    †

     This work was supported by NIH Grant CA79547, the Friends of the Dana-Farber Cancer Institute, and the family and friends of Peter Connaughton.

    ‡

     Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital.

    §

     University of Turin.

    *

     To whom correspondence should be addressed:  Dana-Farber Cancer Institute, Room M552B, 44 Binney Street, Boston, MA 02115. Telephone:  (617) 632-4714. Fax:  (617) 632-6356. E-mail:  [email protected].

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