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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 [http://gocwiki.geneontology.org/index.php/Signaling signaling wiki].

=='''Organization of the signaling node'''==

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

GO:0023052 is separated into [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0035636 multi-organism signaling] (e.g. pheromone signaling between organisms), and [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0044700 single organism signaling]. The GO work so far has focused on single organism signaling, which is further split into [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007267 cell-cell signaling] and 
[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007165 signal transduction] (see below for further details of these groupings)

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

[[File:signaling.png]]

=='''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007267 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.

cell-cell signaling ; GO:0007267 begins with [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0023061 signal release] from the signal-generating cell. Note that [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007165 signal transduction] is limited to events at and within the signal-receiving cell.

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.

'''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0035425 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.

'''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038001 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.

'''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038002 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.

=='''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007165 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 [https://sourceforge.net/p/geneontology/ontology-requests/ SourceForge tracker].

The signaling pathway GO terms are connected to the [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0051716 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). (see below for a diagram of a canonical signaling pathway)

[[File:pathway.png]]


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==='''Signals/Ligands'''===

In a canonical GO signaling pathway, the signal (ligand) is part of the 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 [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0048018 receptor agonist activity ; GO:0048018] or [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0048019 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.'''


[[File:receptor agonist.png]]

The agonist and antagonist terms are also connected to 'receptor activity ; GO:0004872' by regulates relationships. GO includes terms for [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0030546 receptor activators] and [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0030547 receptor inhibitors]. These are broader than the agonist and antagonist terms, and can be used to annotate gene products that regulate a receptor without necessarily activating or initiating a signaling pathway. For example, PMID 8910358 shows that dUTPase, [http://www.uniprot.org/uniprot/P70583 Dut], inhibits the activity of the PPAR-retinoid X receptor by preventing receptor heterodimerization.

A 'glutamate receptor agonist' references a receptor whose natural ligand is glutamate.


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==='''Receptors'''===

The molecular function term [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0004872 receptor activity ; GO:0004872] is divided largely into receptors that respond to a signal ([http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038023 GO:0038023]) and those that  transport a substrate into a cell ([http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038024 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 named 'x-activated receptor activity'

 E.g.
 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 [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0005007 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. 

[[File:hedgehog.png]]


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

 E.g.
 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. For examples of dependence receptors that are part of an apoptotic signaling pathway, see the [http://wiki.geneontology.org/index.php/Apoptosis_Curation_Manual#Signaling_and_execution_phases_of_apoptosis apoptosis curation manual].

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

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

To annotate both these cases, use [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0005007 signal transduction in absence of ligand GO:0038034], and its descendants.



===='''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.

 E.g
 [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0048010 vascular endothelial growth factor receptor signaling pathway ; GO:0048010]
 [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038084 vascular endothelial growth factor signaling pathway ; GO:0038084]
 [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0038086 VEGF-activated platelet-derived growth factor receptor signaling pathway ; GO:0038086]

If you require a new pathway term which states both the ligand and the receptor, please request one using the [https://sourceforge.net/p/geneontology/ontology-requests/ SourceForge tracker].




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==='''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0035556 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 module. A signaling module contains a defined set of signaling events, which are part of a larger signaling pathway.

The intracellular signaling terms are named after the main component that the signal is passed through. For example:

Phosphoinositide 3-kinase (PI3K) phosphorylates PIP2 to PIP3. PI3K lies downstream of a number of receptors including growth factor receptors and GPCRs.
Upon activation, PI3K translocates to the membrane, where it converts phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2, PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P2, PIP3). PIP3 then recruits AKT (PKB) and its activator phosphoinositide-dependent protein kinase-1 (PDK1) to the membrane, leading to phosphorylation and activation of the serine/threonine kinase, AKT (PKB). For a overview of PI3K signaling, see Figure 1 in PMID 23500680.

[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0014065 PI3K signaling] includes any intracellular signaling event, where a signal is passed on through PI3K. This includes effectors upstream of PI3K (e.g. IRS-1) and effectors downstream of PI3K (e.g. AKT/PKB). 

Extracellular ligands (e.g. insulin, growth factors) should be annotated to '[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling].


===='''Intracellular signaling cascades'''====

The term 'cascade' is reserved for signaling modules where the signal is amplified. Examples include [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0000165 MAPK cascade ; GO:0000165] and [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0000165 JAK-STAT cascade ; GO:0007259]


===='''Intracellular signaling modules'''====

Intracellular signaling modules/cassettes will be required for the LEGO annotation model. A signaling module/cassette must contain at least TWO named signaling molecules and therefore a defined start and stop point. 

For example, PI3K-AKT cassette, PI3K-AKT-TOR cassette.



===='''[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0005057 GO:0005057] receptor signaling protein activity'''====

When you know the activity of the intracellular signaling gene product, consider annotating to [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0035556 receptor signaling protein activity ; GO:0005057], or one of the descendents.

 receptor signaling protein activity ; GO:0005057
 --[isa]receptor signaling protein serine/threonine kinase activity ; GO:0004702
 --[isa]receptor signaling protein serine/threonine phosphatase activity ; GO:0009400
 --[isa]receptor signaling protein tyrosine kinase activity ; GO:0004716
 --[isa]receptor signaling protein tyrosine phosphatase activity ; GO:0004728

GO:0005057 and the descendant terms are intended for annotation of intracellular proteins which relay a signal from an upstream receptor, either directly or indirectly.

Example gene products include IRS-1, AKT and PDK1. For a diagram of how these molecules connect upstream receptors to downstream signaling modules, see [http://gocwiki.geneontology.org/index.php/Protein_kinase_B_signaling_cascade_;_GO:0043491]




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==='''The End of a Signaling Pathway'''===

A GO signaling pathway ends with the transfer of information to gene products carrying out a downstream cellular process, for example signaling to the transcription machinery, or signaling to gene products involved in the execution of apoptosis.

The downstream cellular process itself (e.g. transcription or execution of apoptosis) is not part of the signaling pathway, but instead lies downstream of the signaling pathway.


'''S6K example'''

Ribosomal S6 kinase (S6K) is a downstream effector of PI3-kinase (PI3K). S6K phosphorylates the S6 subunit of the 40S ribosome, which enhances translation of some mRNAs. (See Figure 5 in PMID 15122349 for a diagram). S6K would be the last effector in the signaling pathway, passing on the upstream signal to the translation machinery.


'''SREBP1 transcription factor example'''

Sequence-specific transcription factors regulate transcription, as modeled in GO by the regulation parentage of GO:0003700: 

 regulation of transcription, DNA-dependent ; GO:0006355
 --[partof]sequence-specific DNA binding transcription factor activity ; GO:0003700

Transcription factors are therefore often the last participant in a signaling pathway. For example, the transcription factor SREBP1 activates transcription of fatty acid-synthesis genes. EGFR signals through AKT (PKB) to activate SREBP1 (for a diagram, see Figure 7 in PMID 20009104). SREBP1 can therefore be annotated to [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0007173 epidermal growth factor receptor signaling pathway ; GO:0007173'].

The transcription machinery itself is involved in the downstream cellular process of transcription, and is downstream of the signaling pathway.



'''GSK3 example'''

Another critical target of Akt is GSK-3. Glycogen synthesis is regulated in part by GSK-3 which phosphorylates glycogen synthase, inactivating it and preventing the conversion of UDP-glucose to glycogen. AKT phosphorylates and inactivates GSK-3 to relieve the inhibition on glycogen synthase. For a diagram of the signaling events, see Figure 1. in PMID 20087441. 

Although GSK3 is inactivated by AKT, we still consider GSK3 to be a participant in the signaling pathway. 

Glycogen synthase is part of the downstream cellular process of glycogen synthesis, and is therefore not part of the pathway.



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===[http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0015276 GO:0015276] Ligand-Gated Ion Channels===

Not all ligand-gated ion channels are receptors. The ion channels can have receptor activity, if the activating signal originates from outside the cell.


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==Signaling pathways and downstream processes==









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=='''GO IDs'''==

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

PHASE I:
   GOC:mtg_signal
   GO:0023004- GO:0023300, Jen Deegan subrange; signaling

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


[[Category:Annotation]]