STATs: transcriptional control and biological impact

Abstract

Signal transducer and activator of transcription (STAT) proteins are latent in the cytoplasm until activated through receptor-mediated tyrosine phosphorylation — often, but not exclusively by kinases of the JAK family — leading to SH2-domain-dependent dimerization and nuclear translocation. STAT nuclear translocation depends on sequence motifs formed during dimerization, and they remain nuclear until dephosphorylated by a nuclear tyrosine phosphatase, allowing subsequent active nuclear export. So, the most common cycle of STAT activation involves cytoplasmic recruitment to activated cell-surface receptors, tyrosine phosphorylation, receptor release and dimerization, nuclear translocation and DNA binding, coactivator recruitment and gene transcription, nuclear dephosphorylation, and return to the cytoplasm by active nuclear export, followed by possible reactivation due to continued kinase activity. Negative regulators of STATs include cytoplasmic tyrosine phosphatases that counteract Janus kinase (JAK) action, induced suppressor of cytokine signalling (SOCS) proteins that inhibit receptor and JAK function, proteins that inhibit activated STAT (PIAS) proteins that prevent STAT DNA binding, nuclear phosphatases that deactivate STATs, and truncated STAT proteins that can function in a dominant-inhibitory mode. Transcriptional activation of target gene expression relies on coactivator recruitment by STAT transactivation domains, relying on a variety of acetyltransferases, minichromosome maintenance (MCM) proteins, and additional factors yet to be identified. STAT proteins participate in many signalling systems, providing an almost universal paradigm for signalling from cytokine receptors and a commonly used system for growth factor receptors. Target genes dependent on STATs influence growth, survival, apoptosis, host defence, stress and differentiation functions, depending on the signalling pathway and the target tissue. Characterization of JAK and STAT mutations in a variety of organisms, from slime moulds to flies to mice to humans, is beginning to clarify the variety of STAT-dependent biological processes in vivo.