www.landesbioscience.com JAK-STAT e24352-1 JAK-STAT 2:3, e24352; July/August/September 2013; © 2013 Landes Bioscience REVIEW REVIEW REVIEW *Correspondence to: George W Booz; Email: gbooz@umc.edu Submitted: 02/19/13; Revised: 03/18/13; Accepted: 03/18/13 Citation: Zouein FA, Kurdi MM, Booz GW. Dancing rhinos in stilettos: The amazing saga of the genomic and nongenomic actions of STAT3 in the heart. JAK-STAT2013; 2:e24352; http://dx.doi.org/10.4161/jkst.24352 A substantial body of evidence has shown that signal transducer and activator of transcription 3 (STAT3) has an important role in the heart in protecting the myocardium from ischemia and oxidative stress. These actions are attributed to STAT3 functioning as a transcription factor in upregulating cardioprotective genes. Loss of STAT3 has been implicated as well in the pathogenesis of heart failure and, in that context and in addition to the loss of a cardioprotective gene program, nuclear STAT3 has been identiied as a transcriptional repressor important for the normal functioning of the ubiquitin-proteasome system for protein degradation. The later inding establishes a genomic role for STAT3 in controlling cellular homeostasis in cardiac myocytes independent of stress. Surprisingly, although a well-studied area, very few downstream gene targets of STAT3 in the heart have been deinitively identiied. In addition, STAT3 is now known to induce gene expression by noncanonical means that are not well characterized in the heart. On the other hand, recent evidence has shown that STAT3 has important nongenomic actions in cardiac myocytes that afect microtubule stability, mitochondrial respiration, and autophagy. These extranuclear actions of STAT3 involve protein–protein interactions that are incompletely understood, as is their regulation in both the healthy and injured heart. Moreover, how the diverse genomic and nongenomic actions of STAT3 crosstalk with each other is unchartered territory. Here we present an overview of what is and is not known about both the genomic and nongenomic actions of STAT3 in the heart from a structure-function perspective that focuses on the impact of posttranslational modiications and oxidative stress in regulating the actions and interactions of STAT3. Even though we have learnt a great deal about the role played by STAT3 in the heart, much more awaits to be discovered. Dancing rhinos in stilettos The amazing saga of the genomic and nongenomic actions of STAT3 in the heart Fouad A Zouein 1 , Mazen Kurdi 1,2 , and George W Booz 1, * 1 Department of Pharmacology and Toxicology; School of Medicine; and The Jackson Center for Heart Research at UMMC; The Cardiovascular-Renal Research Center; The University of Mississippi Medical Center; Jackson, MS USA; 2 Department of Chemistry and Biochemistry; Faculty of Sciences; Raic Hariri Educational Campus; Lebanese University; Hadath, Lebanon Keywords: JAK, cardiac remodeling, autophagy, posttranslational modification, STAT3, heart failure, redox, microtubule stability, cardiac hypertrophy Introduction First recognized in 1994 as the acute-phase response factor (APRF), 1 signal transducer and activator of transcription 3 (STAT3) is one of 7 mammalian STAT transcription factors that play a central role in signaling by growth factors and cytokines. Of the STATs, STAT3 has a critical nonredundant role in cell growth, survival, and differentiation. The unique importance of STAT3 is underscored by the observation that of the STAT fam- ily members only disruption of the STAT3 gene causes embryonic lethality. 2 Studies over the past 20 years have shown that STAT3 has important actions in protecting the heart under stress. 3-6 In addition, human failing hearts were reported to exhibit reduced STAT3 levels and activity. 7-9 Yet a cohesive understanding of how STAT3 protects the heart has yet to be achieved. The protec- tion afforded by STAT3 has been ascribed to both traditional genomic actions, i.e., the upregulation of protective genes, and more recently some may say fanciful nongenomic actions that target mitochondrial function and autophagy. Neither action is fully understood. Nor is it known how the two are regulated and integrated under either normal or stress conditions. Here we present an overview of what is known and not known about the protective actions of STAT3 in the heart from a structure-func- tion perspective and how posttranslational modifications and oxidative stress may act as determining factors in regulating the genomic and nongenomic actions of STAT3. Overview The STAT3 protein is 770 amino acid in length with 6 distinct domains (Fig. 1). 4 A terminal NH 2 -domain that participates in higher order complex formations that are not well understood is followed by a coiled-coil domain important for protein–protein interaction with other transcription factors and co-regulators. Next, the DNA binding domain canonically interacts with an interferon γ (gamma)-activated sequence (GAS) in the promoter region of specific genes. 10 A subsequent linker domain is located just before a Src homology-2 (SH2) domain that is essential for interaction with specific tyrosine-phosphorylated sites such as the YXXQ sites of the gp130 receptor of the IL-6 type cytokines,