Signaling Curation Manual

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General guidelines for annotating to signaling GO terms

Rationale and aim

The signaling node has undergone a number of large revisions in the past few years. The aim of the most recent work is to clean up and expand the node under GO:0023052 “signaling”, which contained poorly structured and connected terms that did not reflect the current scientific knowledge, and were confusing to curators. In this document we aim to provide a curation guide, starting from the most general terms under 'signaling ; GO:0023052', and progressing to the more specific descendants, hopefully providing a decision tree for GO curators.

For many terms we have added definition comments, to help guide curators. If you think that more terms would benefit from having comments, or their definitions are unclear, please let us know- your suggestions will be very welcome.

The changes and previous revisions can be found on the signaling wiki. The current (October 2013) signaling node is shown below.

Organization of the signaling node

Signaling ; GO:0023052 includes the entire process in which information is transmitted. The start point is an active signal. The end point is triggering of a cellular response (e.g. transcription, apoptotic execution). Note that the end response itself is not part of signaling.

GO:0023052 is separated into multi-organism signaling (e.g. pheromone signaling between organisms), and single organism signaling. The GO work so far has focused on single organism signaling, which is further split into cell-cell signaling and signal transduction (see below for further details of these groupings)

The organization of the signaling node is shown in the figure below:


GO:0007267 cell-cell signaling

cell-cell signaling ; GO:0007267 should be used to annotate gene products where it is known which cell-type generates the signal, and/or which cell-type receives the signal. Signaling between specific cell types is particular important in development when committing cells to a particular cell fate.

Under GO:0007267, are three terms that can be used concurrently with the cell-cell signaling GO terms. Although the parameters of these types of signaling events are sometimes disputed, the GO term definitions were agreed in consultation with signaling experts and annotations should be made appropriately where autocrine/paracrine/endocrine signaling is unambiguous.

autocrine signaling ; GO:0035425 . The signal produced by the signaling cell binds to a receptor on, and affects a cell of the same type. Note that it is not necessarily the SAME CELL, because this is often hard to show in experiments.

paracrine signaling ; GO:0038001. The signal travels from the signal-producing cell to the receiving cell by passive diffusion or bulk flow in intercellular fluid. The signaling cell and the receiving cell are usually in the vicinity of each other.

endocrine signaling ; GO:0038002. An endocrine hormone is transported from the signal-producing cell to the receiving cell via the circulatory system (via blood, lymph or cerebrospinal fluid). The signaling cell and the receiving cell are often distant to each other.

GO:0007165 Signal Transduction

Signal transduction is limited to the events at and within the signal-receiving cell, and covers the specific signaling pathways. Transport of the signal from the signal-generating cell to the signal-receiving cell is therefore upstream of signal transduction.

You should avoid annotating directly to GO:0007165, as the term is very broad. Instead, signaling pathways for specific receptors and ligands are housed under GO:0007165. If you require a new pathway term, please request one using the SourceForge tracker.

The signaling pathway GO terms are connected to the cellular response to stimulus GO terms, since the cellular response includes both the signaling pathway AND the resulting cellular process (e.g. transcription). Note that because ligands are participants in a signaling pathway, annotations to 'response to x ligand', will include the ligand itself.

What is included in a signaling pathway

A canonical signaling pathway begins with ligand-receptor binding, and ends with regulation of a downstream cellular process, often transcription. The end process itself (e.g. transcription, apoptotic execution, cell proliferation, cell differentiation etc) is not considered part of the signaling pathway, but instead lies downstream.

Thefore a signaling pathway includes both the SIGNAL (ligand) and the SIGNAL TRANSDUCERs (receptors and other downstream signaling molecules that pass the signal on).

For a diagram on what gene products are included in a canonical signaling pathway, see below



In GO, the signal (ligand) is part of a signaling pathway. Although signals can be non-coded entities (e.g. light), GO is only concerned with the annotation of protein signals.

Ligand-binding to a receptor can either activate the receptor to initiate a signaling pathway, or inactivate the receptor to switch-off any further signaling. To annotate ligands (e.g. growth factors, cytokines etc), consider annotating to receptor agonist activity ; GO:0048018 or receptor antagonist activity ; GO:0048019. To specify which receptor the signal is activating, consider adding a column 16 annotation, using the relationship: has_regulation_target [UniProt AC]

Note that ligands do NOT have the function signal transducer activity ; GO:0004871.

Receptor agonist.png

The agonist and antagonist terms are also connected to 'receptor activity ; GO:0004872' by regulates relationships. GO includes terms for receptor activators and receptor inhibitors. These are broader than the agonist and antagonist terms, and can be used to annotate gene products that regulate a receptor without activating or initiating a signaling pathway. For example, PMID 8910358 shows that dUTPase, Dut, inhibits the activity of the PPAR-retinoid X receptor by preventing receptor heterodimerization.


The molecular function term receptor activity ; GO:0004872 is divided largely into receptors that respond to a signal (GO:0038023) and those that transport a substrate into a cell (GO:0038024). This curation manual refers to the former.

Receptor GO terms are generally defined in two ways:

i) based on their ligand (e.g. neurotransmitter receptor activity ; GO:0030594). To avoid confusion with gene product names (E.g. EGFR, PDGFR etc), the growth factor receptors are now named 'x-activated receptor activity'

epidermal growth factor-activated receptor activity ; GO:0005006
hepatocyte growth factor-activated receptor activity ; GO:0005008
fibroblast growth factor-activated receptor activity ; GO:0005007

Therefore, if the gene product 'Egfr' binds to, and transmits a signal from FGF, it should be annotated with fibroblast growth factor-activated receptor activity ; GO:0005007.

Where a corresponding binding term exists, the binding term is connected to the receptor activity with a HAS_PART relationship.


ii) the mechanism by which the receptor transmits the signal:

transmembrane signaling receptor activity ; GO:0004888
G-protein coupled receptor activity ; GO:0004930

If you know both the mechanism and the ligand, annotate to the most granular GO term possible.

Dependence Receptors and Basal Signaling

Classical signal transduction is initiated by ligand-receptor interactions. Alternative forms of signal transduction can be initiated by the withdrawal of ligands from specific receptors, referred to as dependence receptors. For more detail, see PMID 15044679.

Basal signaling describes the low-level activity of a receptor in the absence of a ligand.

To annotate both these cases, use ; signal transduction in absence of ligand GO:0038034, and its descendants.

In the case of ligand-withdrawal, the ligand should be annotated to regulation of the signaling pathway, not the signaling pathway itself.

Promiscuous Ligands and Receptors

To reflect where a ligand binds to multiple receptors and where a receptor binds multiple ligands, signaling pathways in GO can be named after the ligand and/or the receptor.

vascular endothelial growth factor receptor signaling pathway ; GO:0048010
vascular endothelial growth factor signaling pathway ; GO:0038084
VEGF-activated platelet-derived growth factor receptor signaling pathway ; GO:0038086

GO:0035556 Intracellular Signal Transduction

GO:0035556 and the descendant terms are to annotate signaling events which occur within the cell, for example gene products that make up an intracellular signaling cascade.

.... to be expanded.

Transcription Factors


Each revision of signaling used a unique set of GO IDs and definition DBXrefs, as follows:


  GO:0023004- GO:0023300, Jen Deegan subrange; signaling


  GOC:mtg_signaling_feb11:	GO content meeting, February 16th-17th 2011.
  GO:0038001- GO:0039000 Becky Foulger subrange; signaling