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The evolutionarily conserved JAK/STAT pathway plays important roles in development and disease processes in humans. Although the signaling process has been well established, we know relatively little about what the relevant target genes are that mediate JAK/STAT activation during development. Here, we have used genome-wide microarrays to identify JAK/STAT targets in the optic lobes of the Drosophila brain and identified 47 genes that are positively regulated by JAK/STAT. About two-thirds of the genes encode proteins that have orthologs in humans. The STAT targets in the optic lobe appear to be different from the targets identified in other tissues, suggesting that JAK/STAT signaling may regulate different target genes in a tissue-specific manner. Functional analysis of Nop56, a cell-autonomous STAT target, revealed an essential role for this gene in the growth and proliferation of neuroepithelial stem cells in the optic lobe and an inhibitory role in lamina neurogenesis.

In their journey to acquire the ability to fertilize the egg, numerous intracellular signaling systems are activated in spermatozoa, leading to an increase in protein tyrosine phosphorylation. Although the JAK/STAT signaling pathway is usually associated with the activation of transcription of specific genes, our laboratory previously demonstrated the presence of the IL6 receptor (IL6R) and the Janus kinase 1 (JAK1) in human spermatozoa, a cell that is mostly transcriptionally inactive. In order to determine the importance of the JAK/STAT signaling pathway, our objectives were to identify and characterize the mediators of this system in human sperm. Cell fractionation and surface biotinylation assays clearly demonstrated that IL6R is expressed at the sperm membrane surface. The kinase JAK1 is enriched in membrane fractions and is activated during human sperm capacitation as suggested by its increase in phosphotyrosine content. Many signal transducer and activator of transcription (STAT) proteins are expressed in human sperm, including STAT1, STAT3, STAT4, STAT5, and STAT6. Among them, only STAT1 and STAT5 were detected in the cytosolic fraction. All the detected STAT proteins were enriched in the cytoskeletal structures. STAT4 was present in the perinuclear theca, whereas JAK1, STAT1, and STAT5 were detected in the fibrous sheath. Indirect immunofluorescence studies showed that JAK1 and STAT1 colocalized in the neck region and that STAT4 is present at the equatorial segment and flagella. The presence of STAT proteins in sperm structural components suggests that their role is different from their well-known transcription factor activity in somatic cells, but further investigations are required to determine their role in sperm function.

Jak/STAT is an important signaling pathway mediating multiple events in development. We describe participation of metazoan co-activator SAYP/PHF10 in this pathway downstream of STAT. The latter, via its activation domain, interacts with the conserved core of SAYP. STAT is associated with the SAYP-containing co-activator complex BTFly and recruits BTFly onto genes. SAYP is necessary for stimulating STAT-driven transcription of numerous genes. Mutation of SAYP leads to maldevelopments similar to those observed in STAT mutants. Thus, SAYP is a novel co-activator mediating the action of STAT.

SIZ1 (for yeast SAP and MIZ1) encodes the sole ortholog of mammalian PIAS (for protein inhibitor of activated STAT) and yeast SIZ SUMO (for small ubiquitin-related modifier) E3 ligases in Arabidopsis (Arabidopsis thaliana). Four conserved motifs in SIZ1 include SAP (for scaffold attachment factor A/B/acinus/PIAS domain), PINIT (for proline-isoleucine-asparagine-isoleucine-threonine), SP-RING (for SIZ/PIAS-RING), and SXS (for serine-X-serine, where X is any amino acid) motifs. SIZ1 contains, in addition, a PHD (for plant homeodomain) typical of plant PIAS proteins. We determined phenotypes of siz1-2 knockout mutants transformed with SIZ1 alleles carrying point mutations in the predicted domains. Domain SP-RING is required for SUMO conjugation activity and nuclear localization of SIZ1. Salicylic acid (SA) accumulation and SA-dependent phenotypes of siz1-2, such as diminished plant size, heightened innate immunity, and abscisic acid inhibition of cotyledon greening, as well as SA-independent basal thermotolerance were not complemented by the altered SP-RING allele of SIZ1. The SXS domain also controlled SA accumulation and was involved in greening and expansion of cotyledons of seedlings germinated in the presence of abscisic acid. Mutations of the PHD zinc finger domain and the PINIT motif affected in vivo SUMOylation. Expression of the PHD and/or PINIT domain mutant alleles of SIZ1 in siz1-2 promoted hypocotyl elongation in response to sugar and light. The various domains of SIZ1 make unique contributions to the plant's ability to cope with its environment.

STAT (signal transducers and activators of transcription) proteins are activated in response to a large number of cytokines, growth factors, and hormones. Upon activation following the binding of ligands to their receptors, STAT proteins dimerize, translocate to the nucleus, and bind to the promoters of specific target genes. To date, seven mammalian members of the STAT family have been identified. Although some cytokines and growth factors can activate multiple STAT proteins, some STATs are activated with considerable specificity. The physiological role of each individual STAT protein is now being examined through the study of "knockout" mice, harboring a null allele for the particular gene. STAT1-deficient mice exhibit a selective signaling defect in response to interferons. STAT4 and STAT6 are essential for Thl-and Th2-responses, respectively. STAT5a-deficient mice exhibit defective mammary gland development. A study of STAT5b-deficient mice indicates that STAT5b mediates the sexually dimorphic effects of growth hormone in the liver. STAT5a and 5b also play different biological roles in the immune system. STAT3-deficient mice die during early embryogenesis, but the role of STAT3 in adult tissues can be assessed by utilizing the CreloxP recombination system to ablate the gene later in life. Analyses of tissue-specific STAT3-deficient mice indicate that STAT3 plays a crucial role in a variety of biological functions, including cell growth, suppression of apoptosis, and cell motility.