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Signal transducer and activator of transcription (STAT) proteins comprise a family of transcription factors that are activated by hormones, cytokines and growth factors. The activation of STAT proteins plays an important role in the production of mature hematopoietic cells via effects on cellular proliferation, survival and lineage-specific differentiation. In mammals, the STAT family consists of STAT1, 2, 3, 4, 5A, 5B and 6, and share a common set of structural domains: N-terminal, DNA binding, SH2, coiled-coil, linker, and transactivation domains. Although the functions are different, the STAT proteins share considerable homology. Besides, crystal structures for full-length proteins or portions of STATs 1, 3, 4 and 6 have been reported and show similarities in structure. Full-length STAT proteins range in size from 90 to 115 kDa and contain several domains that are conserved among all the STATs and are crucial for function.
Non-redundant biological roles of STAT
STAT1 is widely expressed, with high levels in thymus, heart and spleen, STAT4 is found mainly in thymus, testis and spleen, while STAT5a and 5b exhibit differential expression in brain, muscle, mammary gland and secretory organs (salivary gland and seminal vesicles). STAT2, STAT3 and STAT6 are expressed in the majority of tissues.
Stat1-deficient mice show deficiencies in immune responses mediated by IFNα and IFNγ and are highly susceptible to infection with vesicular stomatitis virus and Listeria monocytogenes. The complete lack of responsiveness to interferon corroborated the earlier studies, which had predicted a key role for Stat1 in interferon signaling. Similarly, Stat2-knockout mice are also sensitive to viral infection, with analysis of Stat2-deficient mice and cells confirming a vital role in regulating signaling by the type I interferons. Conditional deletion of Stat3 in adult mouse tissues has shown the importance of Stat3 for a wide range of physiological processes, with defects found in heart, lung, bone, colon, the nervous system and skin, and is consistent with Stat3-inducing biological responses for a large variety of cytokines. Stat4-deficient mice fail to respond to IL-12 and IL-23, leading to reduced Th1 differentiation and natural killer (NK) cell function. Stat5a and Stat5b are required to elicit biological responses to GM-CSF, IL-3, gc cytokines, growth hormone and prolactin. Recently, STAT5 has been found to play additional roles in hemopoietin cell development, differentiation and survival. Stat6-deficient mice are refractory to IL-4 and IL-13 and thus have defective Th2 polarisation, IgG1 and IgE class switching, and greater susceptibility to parasite infection.
JAK/STAT signaling pathway
The Janus kinase/signal transducers and activators for transcription (JAK/STAT) pathway regulate a large number of biological processes including cell proliferation, differentiation, cell migration and apoptosis. The DNA-binding domain determines the DNA-binding specificity for each STAT. The highly conserved Src-homology-2 (SH2) domain recognizes phosphorylated tyrosine residues and thereby mediates interactions between STAT proteins and specific phosphorylated proteins, including growth factor receptors, other STATs and JAK family members (JAK1, JAK2, JAK3 and tyrosine kinase-2 (TYK2)). Ligand binding induces an intracellular activation by the multimerization of different cytokine receptors units, followed by JAKs recruitment to the cytoplasmatic domain of the cytokine receptor. JAK activation occurs when a tyrosine residue in the cytokine receptor is phosphorylated, generating a docking site for cytoplasmic STAT. While STAT proteins are attached to the cytokine receptor, JAK proteins phosphorylate them at a tyrosine residue, detaching the STAT protein from the cytokine receptor so that the STATs form homo- and heterodimers which will translocate to the nucleus and bind DNA sequences to promote gene expression.
Figure 1. Activation of STATs by JAK-dependent and JAK-independent pathways. (Dorritie K A, et al., 2014)
Therapeutic targeting of STAT signaling
The Jak/STAT pathway is important for meeting the diverse challenges faced by the immune system, from resisting infection to maintaining immune tolerance, enforcing barrier functions, and guarding against cancer. In view of the data implicating Jak/STAT in autoimmune disease and malignancy, it is not surprising that this pathway has become an attractive target for pharmaceuticals. Monoclonal antibodies have been developed to target the signaling molecules along the related pathways. Besides, small molecule inhibitors of JAK and Kit are widely used in cancer therapy. Inhibitors targeting STAT molecules, particularly STAT3 and STAT5, are under intensive studies. Unlike Jaks, whose kinase domains are a clear pharmacological target; STATs do not have catalytic activity and, therefore, present a more challenging objective. Oligonucleotide-based STAT inhibitors, which presumably sequester STATs away from “dangerous” loci, are the well-developed method and are undergoing human testing for multiple malignancies. Alternative strategies include small molecule inhibitors, which are also in clinical trials, and STAT-binding “intrabodies,” which have been investigated only in animal models.