Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 44, Pages 33172-33181Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M606940200
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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 onrate 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.
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