STATs in Health and Disease
Signal Transducers and Activators of Transcription (STATs) represent a central paradigm of cell-cell signaling, providing a rapid and effective mechanism to transfer an external signal into a transcriptional response. They act as core components downstrea
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STATs in Health and Disease Clifford Liongue, Rowena S. Lewis, and Alister C. Ward
Abstract Signal Transducers and Activators of Transcription (STATs) represent a central paradigm of cell-cell signaling, providing a rapid and effective mechanism to transfer an external signal into a transcriptional response. They act as core components downstream of a myriad of cytokine and other receptors to mediate a diverse range of functions. This chapter provides an overview of the STAT protein family, their structure, mode of activation, specificity, variants and negative regulation along with their multiple roles in both normal biology as well as the etiology of disease. Keywords Cytokine receptor • Signaling • JAK-STAT • STAT1 • STAT2 • STAT3 • STAT4 • STAT5 • STAT6
1.1
Introduction
Signal Transducers and Activators of Transcription (STATs) were first identified over 20 years ago in the context of interferon signaling [1]. They are now firmly established as one of the most important signaling modalities, particularly in the context of mediating rapid responses of target cells to specific external factors, with a veritable mountain of studies detailing a variety of functions for these transcription factors in a myriad of cell systems across diverse species. STAT proteins play numerous roles in normal biology, particularly within immune and blood cells, and contribute to the etiology of disease, notably including a range of malignancies.
C. Liongue • R.S. Lewis • A.C. Ward (*) School of Medicine, Deakin University, Melbourne, VIC, Australia Centre for Molecular and Medical Research, Deakin University, Melbourne, VIC, Australia e-mail: [email protected]; [email protected]; [email protected] © Springer International Publishing Switzerland 2016 A.C. Ward (ed.), STAT Inhibitors in Cancer, Cancer Drug Discovery and Development, DOI 10.1007/978-3-319-42949-6_1
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C. Liongue et al.
STAT Protein Structure, Regulation and Specificity
Seven STAT proteins are present in humans: STAT1–6, which includes the closely-related STAT5A and STAT5B proteins that are encoded by adjacent but distinct genes [2].
1.2.1
Structure
Each member of the STAT family is composed of several variably conserved domains: the N-terminal, coiled-coil, DNA binding, linker, Src-homology 2 (SH2) and C-terminal domains [3, 4] (Fig. 1.1). The hydrophilic four helix-bundle N-terminal domain has numerous functions, including mediating important proteinprotein interactions and controlling nuclear translocation, the coiled-coil domain regulates the activation of STAT proteins and mediates nuclear export, whereas the β-barrel DNA binding domain is responsible for the interaction with specific DNA sequences. This is connected via a helical linker to a highly conserved SH2 domain that facilitates interactions with phosphotyrosine residues on receptor components as well as other STATs [4]. The so-called ‘transactivation domain’ (TAD) regions at the C-terminus of different STAT proteins show the lowest sequence conservation and contain alte
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