Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas

Abstract

Interaction of cytokines with their cognate receptors leads to the activation of latent transcription factors - the signal transducers and activators of transcription (STAT) proteins - whose biological activities ultimately regulate many critical aspects of cell growth, survival and differentiation. Dysregulation of the JAK-STAT pathway is frequently observed in many primary human tumours, reflecting the importance of this pathway in the maintenance of cellular integrity. Here we review the current progress in STAT structure and function, and the contribution of STAT signalling to the pathogenesis of T-cell lymphomas.

Figure 1

The JAK-signal transducer and activator of transcription (JAK-STAT) signalling pathway. Ligand-induced activation of latent cytoplasmic JAK kinases leads to the docking and subsequent tyrosine phosphorylation of latent monomeric or N-domain-mediated dimeric STAT proteins, facilitating the formation of active SH2-domain-mediated homodimers of STAT proteins. The tyrosine-phosphorylated STAT dimers are actively transported to the nucleus using metabolic energy and the importin α/β and RanGDP complex. Once inside the nucleus, the active STAT dimers bind to the promoters of genes containing the consensus recognition motif (GAS motif-ttcnnngaa) and activate transcription of these genes. STATs can bind DNA as dimers or as N-domain-mediated tetramers. The active STAT protein is only released from DNA upon dephosphorylation by nuclear phosphatases, following cytokine withdrawal, and the inactivated protein is then actively exported out of the nucleus to the cytoplasm by the exportin Crm-1/RanGTP complex. Monomeric STAT proteins can also passively shuttle between the cytoplasm and the nucleus via carrier-free diffusion through nuclear pores facilitated by the interaction with nucleoporins.

Figure 2

Modular structure of signal transducer and activator of transcription (STAT) proteins. All STAT proteins share a common molecular topology and are organized into distinct functional domains. The NH₂ terminus (N-domain) is involved in protein–protein interactions between adjacent STAT dimers on DNA, facilitating the formation of STAT tetramers. It is also involved in the formation of dimers between non-phosphorylated STAT monomers, which is important for receptor-mediated activation and nuclear translocation of certain STAT proteins. Interactions with STAT cofactors, which positively or negatively modulate their transcriptional activity, occurs via the N-domain, the adjacent coiled-coil domain and the carboxy-terminal transactivation domain (TAD). The conserved serine residue (p-S), which is phosphorylated upon cytokine stimulation and is important for maximal transcriptional activation, is located within the transactivation domain. In addition to the full-length form (STATα), STAT proteins can also be present as C-terminally truncated forms generated by alternative splicing (STATβ) or by proteolytic processing (STATγ). The C-termini of STATβ proteins differs from the corresponding STATα protein not only by being truncated but also by having additional amino acids inserted as a result of the splicing event.

Figure 3

Negative regulation of signal transducer and activator of transcription (STAT) signalling. Cytokine-induced STAT activation can be inhibited by SOCS proteins, the gene expression of which is regulated by STAT proteins, thus fulfilling a negative feedback loop. SOCS proteins inhibit STAT activation either by inhibition of the activating JAKs or by competition with STATs for receptor binding. Activated STAT proteins can be dephosphorylated by cytoplasmic and/or nuclear phosphatases. C-terminally truncated STAT proteins, STATβ and STATγ, behave as dominant-negative proteins to functionally compete with their full-length counterparts to alter or inhibit gene expression, respectively. Protein inhibitors of activated STAT proteins (PIAS) interact with STAT proteins to inhibit their DNA binding and/or potentially facilitate their covalent modification by sumoylation and subsequent degradation.