FlyBase:Signaling Pathway Report

Last Updated: 21st May 2019

The ‘Gene Group - Pathway Report’ is a sub-category of our Gene Group resource, which houses functional collections of genes such as complexes and gene families. ‘Pathway Reports’ list genes that have been experimentally shown to act within a pathway or to regulate a pathway. The reports are tailored to display information that may be useful to understanding the role of a particular pathway component or regulator: membership of other Gene Groups, experimentally characterized molecular functions and supporting research papers. Useful links to external resources and publications are provided, as well as options for export and orthology tools.

Pathway Reports are organized in a hierarchical fashion, with a top-level parent report and sub-groups. For the current implementation, pathway sub-groups are divided into 'core', 'positive regulators' and 'negative regulators'. The 'core' set are generally defined as those genes that are required for the activated pathway to function, 'positive regulators' and 'negative regulators' act (directly or indirectly through other regulators) on the core members of the pathway to modify their activity. To add more granularity to some pathways, other groups have been added e.g. upstream pathways, effectors that are negatively regulated by the pathway. These have been provided whilst the resource is under development and may be subject to review.

All Pathway Gene Groups in FlyBase are compiled manually by FlyBase curators, based on research literature, using standards for inclusion agreed by the Gene Ontology consortium. The number of research papers that have been used as evidence for membership gene is shown in the

. These references can be viewed as a hitlist by clicking on the number. The number of pathway references associated with a gene may also help researchers weigh the evidence behind its inclusion. All source references are given in full at the foot of the page.

Buttons are provided to export these member genes to our ‘Batch Download’ tool, if you wish to download associated data (phenotypes, expression data, protein interactions etc.), or to a standard FlyBase HitList, if you want to further refine or analyse the gene list, or to our ortholog tool, DIOPT, to obtain a list of predicted orthologs. The Members table can be customised to order and display information of interest, such as reagents and disease-relevant information. On the parent page for each pathway, an interactive physical network showing regulatory relations and gene product function is provide.

Criteria for pathway membership For each pathway we define a start and an end point. Each pathway report page has a definition and notes that set out how the pathway is defined. For most signaling pathways, the start point will be the binding of an extracellular ligand to a receptor, and the end point will be the binding of a transcription factor to target genes. (Note that for some pathways, such as the Hippo and Notch signaling pathways, this signaling paradigm does not apply.) Genes that are included should directly and specifically be involved in or target the pathway. Genes that have an indirect effect (such as those involved in general cellular processes, such as translation) are excluded, as are transcriptional target genes. In curation, we look for diagnostic assays for typical a pathway e.g. for the Wnt-TCF Signaling Pathway, a TCF/LEF-dependent luciferase reporter assay (TOPflash, PMID:18567805) is often used in cell culture. Each pathway has very different readout assays (i.e. specific phenotypes, gene expression, protein phosphorylation) and the curator uses their judgement and GO annotation rules agreed by the Gene Ontology consortium as to whether enough evidence is presented for inclusion

Below is a field-by-field guide to the information provided in the Pathway Report.

General Information

Name	The FlyBase full name for the Pathway Gene Group.
Symbol	The FlyBase symbol for the Gene Group.
Date last reviewed	Date that the group was created or last reviewed, in format 'YEAR-MONTH-DAY'.
Species	The species for which the Pathway Gene Group has been compiled.
FlyBase ID	The unique identifier for the FlyBase Gene Group (FBgg number).
Number of members	The number of genes in the Pathway Gene Group.

Description

Description	A short textual description of the group, written by FlyBase curators based on the given reference(s). References are hyperlinked to their respective Reference Report in FlyBase or to PubMed.
Notes and selected reviews	May include selected publications for background information, describe the criteria used for inclusion/exclusion or any notes to aid interpretation of pathway membership.
Biological Process Gene Ontology (GO) term(s)	Term(s) from the Biological Process branch of the Gene Ontology that are most relevant to the Pathway Gene Group, hyperlinked to the respective FlyBase 'Term Report'. This term, or a child of it, is used to annotate all member genes.

Related Gene Groups

Parent group(s)	Any immediate parent super-groups within FlyBase are shown here, hyperlinked to their respective Report.
Component group(s)	Any immediate child sub-groups within FlyBase are shown here, hyperlinked to their respective Report.
Other related group(s)	Any non-protein complex groups within FlyBase that are related to the current Pathway but not through a parent-child relationship (e.g. ligands-receptors, enzymes-substrates) are shown here, hyperlinked to their respective Gene Group Report.
Protein Complex group(s)	Any protein complex groups within FlyBase that act in the featured pathway but not through a parent-child relationship are shown here, hyperlinked to their respective Gene Group Report.

Physical Interaction Network

1. How are the networks generated?

The networks are generated using Cytoscape, using FlyBase-curated physical interaction data to make connections between genes listed in the Members Table.

2. How do I change the layout of the network?

The layout of the network can be changed by either clicking the 'Reset' button or clicking on and dragging nodes. Two viewing options are available: a pathway view, which distinguishes regulatory interactors, and a functional view, which colors nodes depending on the functional class of the gene product. The layout is maintained when switching between views.

3. What does the node size represent?

Node size reflects the extent of supporting evidence for a gene's involvement in or with a pathway. The node size is calculated based on the number of papers that FlyBase has curated using the Gene Ontology indicating that there is experimental evidence for that gene's involvement with that pathway (as indicated in the Members Table, # Refs column). The node size does not increase beyond a count of 10 papers.

4. Are all physical interactions shown?

No. Self-association interactions are excluded. Regulatory ncRNAs (triangular nodes) are shown as interacting with target protein nodes rather the target mRNA, to illustrate where they impinge on the pathway.

5. Are all genes in the Members Table shown in the network diagram?

Only genes that have curated physical interaction data between members are shown. This can mean that some pathway members are not shown or that some groups of genes can seem isolated from the network. Future plans are to add new types of experimental data to help fill these gaps, where possible. An important aspect of these networks is that they reflect experimental evidence. As new experimental data is curated, the networks will be updated.

6. What is a 'Context-dependent Regulator'?

A context-dependent regulator has been shown to act both as a positive and a negative regulator and are colored white in the pathway view. Note, if an gene has been shown as both part of the core pathway and to regulate the pathway, it is colored as a core member.

7. How are the functional classes assigned?

Genes are classified based on their membership of a Gene Group.

Functional Class - Gene Group

Ligand - RECEPTOR LIGANDS

Receptor - TRANSMEMBRANE RECEPTORS

Kinase - PROTEIN KINASES

Phosphatase - PROTEIN PHOSPHATASES

Ubiquitin Ligase - E3 UBIQUITIN LIGASES

Deubiquitinase - DEUBIQUITINASES

Transcription Factor - TRANSCRIPTION FACTORS (note that these only include DNA-binding transcription factors)

Where the gene belongs to two of these Gene Groups, the following rules are applied:

a) whenever a gene is both a kinase and a receptor, it is shown as a receptor (e.g. InR);

b) whenever a gene is both a ligand and a receptor, it is shown as a ligand (e.g. boss);

c) whenever a gene is both a phosphatase and a receptor, it is shown as a phosphatase (e.g. Ptp4E)

Members

The Members table lists all member genes of the current Gene Group and any subgroups - subgroups are partitioned into individual subsections, the title bar of which is hyperlinked to the Gene Group Report for that subgroup. Member genes are listed alphabetically within each subsection

For all members

View Orthologs	Runs the list of genes through the QuickSearch Orthologs tool, and displays a list of orthologs from human and several different model organisms.
Export to HitList	Export all genes in the Members Table to a standard FlyBase HitList, which allows further refinement and analysis of the gene list.
Export to Batch Download	Export all genes in the Members Table to the FlyBase 'Batch Download' tool, which allows bulk download of any associated data fields.

Members Table

The table can be customised to order and display information of interest. Columns can be added or removed using the Show/Hide Column button and arranged horizontally by dragging columns. To sort vertically on the data in the column, mouse-over the column header and use the arrow button. The column header text box can be used to only display the genes that have matching text in the column field. By default, the first five columns listed below are shown.

Gene Symbol	The FlyBase symbol for the gene, hyperlinked to the Gene Report for that gene.
Gene Name	The FlyBase full name for the gene.
Gene Group Membership	Gene Groups to which gene belongs. (This may or may not relate the gene product's role in the featured pathway.)
GO Molecular Function (Experimental)	Any Molecular Function term or terms from the Gene Ontology (GO) that have been assigned to the gene based on experimental evidence. (This may or may not relate the gene product's activity in the featured pathway.)
# Pathway Refs	Number of research publications that have been manually annotated using the Gene Ontology to indicate that they contain experimental evidence to support a gene's involvement in a pathway. (This can be used to infer the extent of direct experimental evidence for supporting a gene's involvement in a pathway.)
# All Research Refs	Number of research publications that discuss the gene in any context.
Also Known As	A list of up to five commonly used symbol synonyms for the gene. (This list is made computationally, based on the frequency of alternative symbols that have been curated from the literature.)
Antibody	Indicates whether an antibody to the gene product has been curated by FlyBase. Links to Stocks and Reagents section of the Gene report which contains an Antibody Information subsection.
Classical/Insertion Alleles	Number of classical and insertion alleles for gene. Links to Alleles, Insertions and Transgenic Constructs section of the Gene report which contains a Classical and Insertion Alleles subsection.
Transgenic Constructs	Number of transgenic constructs for gene. Links to Alleles, Insertions and Transgenic Constructs section of the Gene report which contains a Transgenic Constructs subsection.
Disease Models (Experimental)	List of diseases showing human disease(s) that are being modelled by a given mutant or transgenic allele. A more detailed table is available on the Disease Ontology (DO) Annotations section of the Gene report.
Potential Disease Models (Orthology)	List of diseases showing human disease(s) that are associated with the human ortholog of the given D. melanogaster gene (only when ortholog calls are supported by at least 3 algorithms). A more detailed table is available on the Disease Ontology (DO) Annotations section of the Gene report.
Other pathways	Other FlyBase Pathway groups that the gene has been associated with.
Human orthologs	Orthology calls between D. melanogaster and human, as provided by the DRSC Integrative Ortholog Prediction Tool (DIOPT). Only ortholog calls supported by at least 3 algorithms are shown.

External Data

Other resource(s)

The name of any other specialist websites relevant to the pathway, hyperlinked to that resource. The type of resource is indicated e.g. Summary Text, Illustration, Reactome Pathway.

Synonyms and Secondary IDs

Synonyms(s)	Alternative commonly used symbols/names used in Drosophila literature and/or the wider field to refer the Pathway Gene Group.
Secondary FlyBase ID(s)	Any non-current FlyBase Gene Group ID(s) (FBgg numbers) that have been used previously to refer to the Pathway Gene Group but which have retired for some reason (e.g. a new FBgg number is assigned if two or more Gene Groups are merged, or if a single Gene Group is split into separate groups).

References

The full citations of all references used to compile the group, organised by publication type, and hyperlinked to their respective Reference Reports.