The role of understudied post‐translational modifications for the behavior and function of Signal Transducer and Activator of Transcription 3 (original) (raw)
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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in multiple fundamental biological processes and a key player in cancer development and progression. STAT3 is activated upon tyrosine phosphorylation and is constitutively active in various malignancies; therefore, the expression of pSTAT3 has been recognized as a predictor of poor survival. STAT3 encodes two alternativelyspliced STAT3 isoforms: the full-length STAT3α isoform and the truncated STAT3β isoform. These isoforms have been suggested as the reason for the occasionally observed opposing roles of STAT3 in cancer: an oncogene, on one hand, and a tumor suppressor on the other. To investigate their roles in aggressive breast cancer, we separately silenced each isoform and found that they affect each other's activation, impacting cell viability, cytokine expression, and migration. Silencing specific isoforms can lead to a more favorable balance of activated STAT3 proteins in the cell. Distinguishing between the two isoforms and their active forms is crucial for STAT3-related cancer diagnosis and therapy.
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RT Reverse transcriptase STAT3 Signal Transducer and Activator of Transcription 3 WT Wild-type Signal Transducer and Activator of Transcription 3 (STAT3) is a pleiotropic transcription factor playing essential roles in normal development, immunity, response to stress/damage and cancer [1, 2]. Latent STAT3 monomers and homodimers shuttle between the cytoplasm and the nucleus [3]. Activation of STAT3 by various types of extracellular signals, such as the IL-6 family of cytokines, triggers the accumulation of STAT3 dimers in the nucleus and the transcription of a specific set of genes [4, 5]. Phosphorylation at Y705 is commonly considered the canonical, rate-limiting step for STAT3 dimerization, nuclear translocation, DNA binding and transcriptional activation [6, 7]. However, unphosphorylated STAT3 (at Y705) also dimerizes, is present in the nucleus, binds to DNA and activates a specific set of genes different from Y705-phosphorylated STAT3 [8-11].
2012
Phosphorylation of STAT3 (signal transducer and activator of transcription 3) is critical for its nuclear import and transcriptional activity. Although a shorter STAT3β spliceform was initially described as a negative regulator of STAT3α, gene knockout studies have revealed that both forms play critical roles. We have expressed STAT3α and STAT3β at comparable levels to facilitate a direct comparison of their functional effects, and have shown their different cytokine-stimulated kinetics of phosphorylation and nuclear translocation. Notably, the sustained nuclear translocation and phosphorylation of STAT3β following cytokine exposure contrasted with a transient nuclear translocation and phosphorylation of STAT3α. Importantly, coexpression of the spliceforms revealed that STAT3β enhanced and prolonged the phosphorylation and nuclear retention of STAT3α, but a STAT3β R609L mutant, with a disrupted SH2 (Src homology 2) domain, was not tyrosine phosphorylated following cytokine stimulation and could not cross-regulate STAT3α. The physiological importance of prolonged phosphorylation and nuclear retention was indicated by transcriptome profiling of STAT3 − / − cells expressing either STAT3α or STAT3β, revealing the complexity of genes that are up-and down-regulated by the STAT3 spliceforms, including a distinct set of STAT3βspecific genes regulated under basal conditions and after cytokine stimulation. These results highlight STAT3β as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3α phosphorylation and nuclear retention after cytokine stimulation.
Signal Transducer and Activator of Transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus-STAT3 bimolecular fluorescence complementation (BiFC) assay that allows the visualization and study of STAT3 dimerization and protein-protein interactions in living cells. Inactivating mutations on residues susceptible to post-translational modifications (K49R, K140R, K685R, Y705F and S727A) did not alter the basal dimerization of unstimulated STAT3, but changed significantly the intracellular distribution of STAT3 dimers. Surprisingly, the distribution of specific asymmetric STAT3 dimers (i.e. the STAT3 molecules carry different mutations) was different from symmetric dimers. Our results indicate that asymmetric post-translational modifications on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. This set of Venus-STAT3 BiFC...
Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T
Proceedings of the National Academy of Sciences, 2007
Protein tyrosine phosphatase (PTP) receptor T (PTPRT) is the most frequently mutated PTP in human cancers. However, the cell signaling pathways regulated by PTPRT have not yet been elucidated. Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. Accordingly, overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes. These studies illuminate a mechanism regulating the STAT3 pathway and suggest that this signaling pathway plays an important role in colorectal tumorigenesis.