STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer

Abstract

STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this 'canonical' paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate 'non-canonical' functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.

Keywords: Cancer; Cytokine; Immunity; JAK; STAT; Transcription factor.

Fig. 1

Structure of STAT proteins. Schematic illustration of a representative STAT protein showing its six conserved functional domains: N-terminal, coiled-coil, DNA-binding, linker, Src-homology 2 (SH2) and C-terminal. The positions of a nuclear localization signal (NLS) and tyrosine (Y) and serine (S) residues phosphorylated in response to extracellular stimuli are shown, along with the sites of interaction of various transcriptional co-activators (green) and co-repressors (red)

Fig. 2

Canonical STAT mode of action. Schematic representation of the archetypal ‘canonical’ STAT functional modality and its control. In this paradigm, STAT proteins (orange/yellow) exist in the cytoplasm as latent, unphosphorylated STAT (uSTAT) molecules. In response to binding of their cognate extracellular ligands (light pink), transmembrane receptors (dark blue) undergo conformational changes that results in the activation of kinases such as the receptor-associated JAKs (light brown), which subsequently mediate phosphorylation (P, green) of tyrosine residues within the intracellular receptor complex, thereby creating docking sites for signaling molecules, including uSTATs. These in turn become tyrosine phosphorylated, with the phosphorylated (pSTAT) molecules able to form dimers that can translocate into the nucleus and bind to specific DNA sequences (blue) to activate the transcription of responsive genes. These encode effector proteins (brown) responsible for cell differentiation, proliferation, survival and activation, as well as SOCS proteins (blue). These mediate a negative feedback loop by blocking STAT activation through interfering with STAT docking, inhibiting JAKs and/or mediating degradation of receptor signaling components. Other negative regulators include PIAS proteins (grey blue) that act via blocking STAT dimerization and nuclear entry and Protein tyrosine phosphatase (PTP) proteins (orange) that can dephosphorylate receptor complex components in the cytoplasm as well as pSTAT molecules in the nucleus to regenerate uSTAT molecules that return to the cytoplasm

Fig. 3

Alternative STAT functional modalities. Schematic depiction of alternate modes by which STATs can impact on cellular functions: A inducible transcriptional activation (‘canonical’ signaling), B inducible transcriptional repression, C basal transcriptional activation, D basal transcriptional repression, E inducible non-nuclear function, F basal non-nuclear function. Shown are unphosphorylated STAT (uSTAT) molecules and their conversion into phosphorylated STAT (pSTAT) molecules and their dimerization where appropriate, as well as their movement between the cytoplasm, nucleus and other cellular compartments, along with the molecular function(s) that they exert in each case