Focus Issue: Building Signaling Connections

The STKE Connections Maps database continues to flourish, with new canonical and specific pathways being added throughout the year, and the existing pathways being updated continuously. This year's Special Issue, published in conjunction with a series of Viewpoints in Science , highlights new canonical pathways in immunology [Interleukin 4 (IL-4) and IL-13 Pathways by Kelly-Welch et al . and the Toll-Like Receptor (TLR) Pathway by Barton and Medzhitov], as well as new canonical and specific pathways in neurobiology (Circadian Rhythm Pathways by Van Gelder and Granule Cell Survival Pathway by Leuillet et al .). In addition, the seven transmembrane family of receptors, which most often couple to heterotrimeric guanine nucleotide-binding proteins (G proteins) and are therefore best known as G protein-coupled receptors (GPCRs), are represented with new pathways and Viewpoints. These new pathways, which complement the existing Gαi, Gαs, Gαq, Gα12, and Gα13 seven transmembrane receptor signaling pathways by Iyengar and colleagues, include examples of G protein-independent signaling, as well as signaling pathways mediated by G proteins. Both a canonical and a specific pathway by Kimmel and Parent focus attention on the persistence of signaling from seven transmembrane adenosine 3′,5′ monophosphate (cAMP) receptors even in Dictyostelium discoidium deficient in various G protein genes. Kimmel and Parent also provide a pathway describing the D. discoidium G protein-mediated chemotactic response to cAMP. The seven transmembrane receptor signaling pathways also include a new pathway for Wnt signaling that describes emerging evidence that certain isoforms of Frizzled receptors--best known for their G protein-independent regulation of β-catenin stability and activation of β-catenin as a transcriptional regulator in response to Wnt--can also signal through G proteins to regulate intracellular calcium and guanosine 3′,5′-monophosphate (cGMP) concentrations. Finally, adrenoreceptor signaling, which has important clinical implications in heart disease, is featured in canonical and myocyte-specific pathways by Xiang and Kobilka. As the database grows, an intricate network linking the different signaling pathways begins to emerge. The connections between pathways are depicted with two different sorts of navigational tools. (For more details about the database structure and navigating to the underlying data records, please see the [Connections Maps help][1].) "Interpath links" are defined by the Pathway Authorities, who identify signaling components and cascades that are shared by more than one pathway. For example, the TLR Pathway has an interpath link to the Type 1 Interferon (α/β) Pathway. Genes expressed in response to TLR activation include the ligands that activate the receptors in the Type 1 Interferon (α/β) Pathway. With the current graphical display options, in the TLR pathway map, the IFNa/b "node" is designated with a diamond shape to indicate that it also participates in another pathway. Clicking on the IFNα/β "node" takes you to the type1 IFN Pathway, and, if you have chosen to use the scalable vector graphics (SVG) display option, a red relation arrow indicates that you have arrived at this pathway diagram through an interpath link from the diamond-shaped IFNα/β node. Additional interpath links can be found between the D. discoidium cAMP receptor pathways and between the IL-4 and IL-13 pathways, which share a receptor. Pathway Walking is a different way to explore connections between pathways. In this case, as components in the database are incorporated into multiple pathways, all the other components with which a given component interacts and all of the pathways in which these interactions occur are displayed in tables in the pathway-dependent component records. One can also see the pathways in which a component participates in a table in the pathway-independent component records. Pathway Walking thus begins to uncover the signaling "hubs" and the network properties of the cellular signaling world. To increase the ability of the STKE users to visualize the dynamic nature of several of these signaling pathways, animations have been created to accompany several of the pathways. These include a general animation and a mammalian-specific animation of central circadian oscillators, as well as an animation of the reorganization of signaling components and cytoskeletal elements that occurs during D. discoidium polarization and chemotaxis in shallow chemoattractant gradients. In addition, new schematics and movies showing cellular responses to various extracellular factors have been added for the PC12 Cell Differentiation Pathway, the Granule Cell Survival Pathway, and the T Cell Receptor Pathway. As the database matures and more pathways and components are added, STKE will begin building new tools and features that allow the scientific and education communities to manipulate, customize, and experiment with the Connections Maps. The STKE editors welcome your comments and suggestions about new tools and features; just use the Feedback link to send us a message. The Pathway Authorities welcome comments about new findings that may impact a pathway or about the data that comprises the components and relations in the pathways. These pathways continue to be dynamic, with the pathway data being updated, new pathways and components being added, and the pathway display being generated algorithmically as a graphical representation of the information in an ever-evolving database. Featured in This Focus Issue Related Resources [1]: http://stke.sciencemag.org/help/index.dtl?page=cm