Binding of a cytokine or growth factor induces dimerization of its receptor. JAK tyrosine kinases are then recruited to these dimerized receptor complexes. JAKs are activated by transphosphorylation and subsequently phosphorylate and activate STATs latent transcription factors that reside in the cytoplasm until activated.
There are seven mammalian STATs that, upon phosphorylation, dimerize and enter the nucleus, where they bind specific regulatory sequences to activate or repress the transcription of target genes [ 49 ]. These cells express multiple subtypes of P2X and P2Y receptors. These effects were rapid and transient with maximal phosphorylation evident 15 min following exposure to ATP.
However, due to lack of specificity of these antagonists, it is difficult to interpret these findings. Evidence is accumulating that specific P2 receptors are involved in the regulation of proliferation, differentiation, activity and survival of immune and related cell types through the activation of distinct transcription factors.
The lack of selective agonists and antagonists for many subtypes of P2 receptors has made it difficult to assess their specific roles. Development of genetically modified mouse models in which receptor subtypes are over-expressed or deleted will provide critical information on the transcriptional effects of specific subtypes of P2 receptors. Such information will be instrumental in determining the roles of these receptors in inflammation and immunity, as well as related processes such as osteoclastic bone resorption [ 52 ].
This knowledge may lead to the identification of P2 receptors or components of their downstream signaling pathways as targets for therapeutic intervention in inflammatory and immune disorders. Leukocytes express multiple subtypes of P2X and P2Y receptors that play diverse roles in regulating the development of the immune system and in modulating inflammatory and immune responses.
Although great progress has been made in sorting out many of the initial signaling events triggered by activation of P2 receptors, relatively little is understood about their role in transcriptional regulation. Given the availability of high throughput transcription factor arrays, ChIP and reporter assay screens, rapid progress in this field is expected. Further studies are clearly needed to elucidate the effects of nucleotides on the transcriptional machinery of various immune cell types, and interactions with pathways activated by cytokines, growth factors, extracellular matrix and other stimuli.
The transcriptional effects of nucleotides will undoubtedly depend on the nature of the stimulus, P2 receptor expression, cell type and cellular environment. Therefore, the actions of nucleotides on processes such as proliferation and differentiation must eventually be considered within the context of a complex dynamic network of signaling pathways that are activated in spatially and temporally distinct patterns.
We thank Frank Beier, Suzanne M. We are also grateful to investigators in this rapidly advancing field for permission to reproduce illustrative material from their previously published work.
We apologize to those scientists whose findings were omitted due to space constraints or to oversight. National Center for Biotechnology Information , U. Journal List Purinergic Signal v. Purinergic Signal. Published online Jan 3. Sims , and S. Jeffrey Dixon. Stephen M.
Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Feb 22; Accepted Mar This article has been cited by other articles in PMC. Abstract Extracellular nucleotides, acting through P2 receptors, can regulate gene expression via intracellular signaling pathways that control the activity of transcription factors.
Introduction Extracellular stimuli regulate gene expression via intracellular signaling cascades that control the activity of transcription factors.
Table 1 Regulation of transcription factor activity in immune and related cell types by extracellular nucleotides. Open in a separate window. Methods for assessing activation of inducible transcription factors Several approaches can be used to detect the activation of transcription factors. Figure 2. Figure 3a—e. Figure 4a—e. Activator protein 1 AP-1 family of transcription factors AP-1 is composed of structurally and functionally related members of the Jun and Fos protein families.
Nuclear factor of activated T-cells NFAT family of transcription factors NFAT is a family of transcription factors that regulate the differentiation and activation of a number of immune and related cell types, including T-cells and osteoclasts [ 7 , 8 ].
Figure 5. Concluding remarks Evidence is accumulating that specific P2 receptors are involved in the regulation of proliferation, differentiation, activity and survival of immune and related cell types through the activation of distinct transcription factors. Footnotes 1 Since preparation of this manuscript, an excellent review has been published on the regulation of MAP kinases and transcription factors by P2 receptors in microglial cells [ 53 ].
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