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J. Biol. Chem., Vol. 281, Issue 44, 33172-33181, November 3, 2006

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Elevated Activity of STAT3C due to Higher DNA Binding Affinity of Phosphotyrosine Dimer Rather than Covalent Dimer Formation^*

From the Centre for Biochemistry and Cell Biology, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom

Signal transducer and activator of transcription (STAT) proteins are involved in cell proliferation and survival, aspects of tissue differentiation and immune function. STAT3 appears to be fundamentally important for vertebrate organisms, being required for the self-renewal of embryonal stem cells in response to leukemia inhibitory factor signaling and for proliferation of some somatic cell types. Moreover, STAT3 is up-regulated in a range of tumors, and a modified version of STAT3 (STAT3C) has been shown to function as an oncogene, whereas inhibition of STAT3 can suppress tumor cell growth. The constitutive activity of oncogenic STAT3C was reported to depend on spontaneous dimerization directed by disulfide bonds in the absence of tyrosine phosphorylation. In fact, tyrosine phosphorylation consequent upon cytokine or mitogen-induced signaling events remains obligatory for STAT3C activation. Instead, the DNA-binding affinity of phospho-STAT3C is elevated resulting in a faster on-rate and slower off-rate. The faster on-rate sensitizes STAT3C to cytokine stimulation, and the slower off-rate protects it from inactivation by nuclear phosphatases. These changes account for the ability of STAT3C to up-regulate persistently the expression of STAT3 target genes and promote cell cycle progression.

Received for publication, July 21, 2006 , and in revised form, August 23, 2006.

^* This work was supported by an Association for International Cancer Research (AICR) grant (to P. E. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 44-115-82-30-120; Fax: 44-115-82-30-146; E-mail: peter.shaw{at}nottingham.ac.uk.

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