Talk:Signaling Workshop February 2011

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Full Signalling mtg minutes

SO-Sandra Orchard; VW-Val Wood; AT-Andrea Townsend; RL-Ruth Lovering; RF- Becky Foulger; PD-Peter D’Eustachio; MH-Midori Harris; PR-Paola Roncaglia; VK-Varsha Khodiyar; ST-Susan Tweedie; AC-Andrew Chatr-aryamontri SJ-Steve Jupe

Where does signalling begin?

SO – overlap between end of one pathway with start of next, if you go from ligand to production of ligand

VW – would you expect TFs in signalling pathways?

AT – no, would not expect TF’s in a pathway

VW – initiation of a signal is when the ligand exists

AT – end step is production of ligand

RL – would want to capture assoc processes with a TF, e.g. TF is inv in response to glucose

VW – TF’s would be regulating the process

RF – need to distinguish signaling vs signal transduction

AT – endocrine process, autocrine and paracrine is similar, just depends on how far signal has to travel

PD – need to be able to predict what proteins are inv in each pathway

AT – do we use a ref dictionary, one source of defs?

MH – we tend to strat with Oxford dictionary, but need to depart from it for quite a few terms, maybe cos dict is out of date, and GO has extended beyond dict scope.

AT – do we need signaling as a high order term?

RF – it is a grouping term, we have different types of signaling under it

AT – we have autocrine, but not paracrine or endocrine. Terms were created as needed, not created on a top down basis

RF – need to say where does the signal come from? Need to extend signaling upstream beyond just having the ligand

AT – root path is not defined, some very specific, some not so

ALL – will be worked on over time

RF – signaling does not inc production of ligand, but does inc transport of signal from originating cell to cell in which signal transation happens

Transport of signal

VW – want to capture what TF does, e.g. reg of x signaling – ALL agrees

PR – as user of GO annot, just need to know that something is inv in a process, don’t need to know specific?

RF – reg of signaling does not make sense, but is a grouping term

AT - Secretion is it’s own process, keep it separate

PD – secretion/signal release if part of signaling

RF – signal release is part of signalling – all agree Signal release is upstream of pathway

Gen of sig release is no longer part of cell-cell signaling

Defn of a signal is something that triggers a change in a cell.

AO – signal should be a child term of stimulus. Signal transduction is a child of

AT – do we have a term signal, what is def of this? Can we have a GO dict, separate to the GO?

PD – this would be incredibly helpful. What does GO mean by signal?

All agree that this would be useful.

SO – this could go in comment of signaling

PD – glossary of GO terms on a wiki page

VK – hyperlink to signal term from def of each term

MH – need to contact developers of each tool to suggest that

OUTCOME: def of signal agreed and added to comment field in signaling term

RH – will this be linked from other signaling terms?

RF- does signaling include secretion of signal?

ST – signal maturation is considered a reg of pathway.

RL – ligand released in an inactive form, is that inc in signaling?

RF – signaling starts with an active molecule, in some cases it might need processing, in which case it regulates the process.

So need to be woolly in def of signaling, OUTCOME: transport of signal between cells inc in signaling OUTCOME: signaling begins with an active signal

Need to decide on whether secretion of signal is part of signaling, as not all signals are secreted in active form. Synthesis of signal is NOT part of signaling

ACTION: Can generation of signal be obs or moved, need to look at children

Endocrine vs Paracrine

Should we distinguish between these terms? Endocrinologist reaction was mixed, some said fine to split, some said not possible to tell.

AT – Endocrine requires hormone, and goes into circulatory system. Paracrine signal goes into intracelleuar space.

RF – these distinctions are in the defs already. Autocrine – is in GO, but not always possible to tell it is coming back to the same cell.

RL – how would you do the expt to check autocrine vs paracrine?

AT – expts not likely to be repeated. Endocrine sig imp as needs an intact organism to work. Auto/para not so imp.

RL – would seem odd to remove auto/para as need to be consistent

RF – ok to have terms and rely on annotator to decide?

RL – use authors intent in expt to decide which term to use.

AT – can you really distinguish between auto and para? These types of signaling are shown in intact organisms, not in cell based assays.

RF – add comment that these terms should be used with caution, when def fits.

AT – if you see FGF release, could annotate to paracrine sig, when unsure what receptor was activated?

AD – No direct annots to generation of signal

Start and end of signaling process

RF – signal transduction is child of cellular response to stimulus. Pathway ends with downstream cellular process, eg. Reg of transcript, reg of apop,

AT – so inc change in cell fate, or cell activity?

RF – cellular priocess would be transcript, cell division would be too far downstream

AT – need to have gross measurable reponse

AT – lots of pathways that impact TF of PKA and PFC.

RF – cyclic AMP we have as a mid-pathway cassette Upreg and activation of TF is part of pathway, but the TF itself is not part of the pathway.

AT – people measure gene expression to gauge pathway activation.

ST – FOXO considered part of sigaling pathway by authors. But FOXO is a TF.

RF - we don’t annotate GO terms to target, we annotate what acts on the target. Resposne to terms are used for

RL – Map kinase pathway – the last kinase is not part of the pathway, as it is the last kinase in the cascade. Wants ligand to be inc in pathway, eg. Insulin be to be in insulin pathway. Likewise people want the last molec to be inc in the pathway.

AT – might be better to be more inc than exclusive

PD – if we know input acts on more than one family of genes, with well defined output, we don’t know what to annotate to?

RL – make activation of TF last step of the pathway, which then leads to transcription TF act in transcription process, and also reg transcript.

RF – see manual, pg 10 Glycogen synthesis is NOT part of insulin pathway, so how is this different from transcription?

VW- seq specific TF always reg transcription, never part of the process. So these TFs should be part of the pathway.

AT – agrees with VW.

RF – prob is linking upstream and downstream event in the ontolog is problematice bcuase of ontology structure.

RL – TF is part of signal transduction, is taking the signal from kinase to the promoter on the DNA. So is last step in pathway.

RF – don’t want transcription as part of signaling

RF – annotate TF to transcript or reg of transcrip?

AT – use signal test, is this still conveying information?

RF – summary, so FOXO is still conveying info, glycogen synthase is not.

PD – rtwo parts to TF, core promotor, only aim to bing RNAP pol II. Then there are specialist modulating factors which reg RNA pol II. If ssTF not allowed to belong to both, then ssTF reg transcription.

AT – ssTF are not part of transcription machinery.

RF – summary, signal does not end with FOXO.

MH – reg transcription is one of the outcomes.

AT – signal stops when the proicess becomes

ACTION – talk to Karen about whether ssTFs need to be under reg of transcript or direct transcript. What is diff between ssTF and core promoter recognizing TFs?

RF – first signal transducer would be receptor alone?

PD – the first signal transducer would be receptor-ligand complex.

RF – ligand is signal, and is inv in signal transduction too.

RL – is complement cascade considered a signalling event? OUTCOME: def of signal transduction agreed

ACTION: state in comments and signaling manual that core RNA pol proteins should NOT be annotated to the signal transduction term. - DONE

Initiation of signal transduction

Check children of sig transducer activity to see if they have other parents.

Afternoon session

Definition of initiation of signal transduction ; GO:0023036

Comment and def are not consistent.

AT: quoted Oxford def of signal transduction - includes 'extracelluar'

Discussion of whether signal is always extracellular or not.

AT: Even calcium signaling starts from the outside of the cell.

RL: although calcium started outside the cell - event to get it in wasn't necc a signaling process. If release from intracellular store is the initiation of signal then it doesn't start outside the cell.

MH: better to take extracellular out of the def since that doesn’t exclude those that are extracelllular - not confident that there will never be an intracellular signal.

AT: signal transduction is traditionally from an extracellular signal - classical def.

BF: do we even need this term? Given that receptor can't go under it since the def ends with activation of receptor

VW: septation initiation network doesn’t start with an extracellular signal

AT: will end up with broad term that isn't used (that doesn't specify location) and narrow child that does - corresponding to the classical def of signal transduction

VW: sin initiates on spindle pole body

RL: Heterodimer one has ligand binding activity other doesn't but arent' they both involved in initation of signal transduction

BF:Where does it end? When it is passed onto next molecule?

AT: I would never use this term - only any use for something completely novel. when signal is attenuated - termination of initation of st

VW: isn't this positive reg of signal trans?

RL: if we have intracellular cassettes what will be annotated with this e.g. RIS will that be part of a cascade or to this term? Are initation and termination cassettes - will there be overlap between lots of modules?

General : no these are not cassettes they are events

BF: if it just has receptor and ligand it is pointless - if it goes on further we can't define to where - Obsolete it

PD: makes it harder to define end of this over G coupled receptors etc etc

AT: if we can't understand it get rid of it!

BF: children of it… are they better as function e.g. light activated receptor activity?

Has it been used? Probably not since it was made by the working group cos is seemed a good idea at the time. 6 current annotations - all to children - all better as receptor activities.

Termination of signal tranduction

AT: don't like it as it is ambiguous - depends where you look. also hasn't been used

AI: obsolete this term Termination of signal tranduction

VW: like saying final step of pathway x - meaningless This is different from attenuation - which comes under neg reg of signal t.

MH: better when these sort of things come from natural usage.

AI: obsolete initiation of signal transduction - existing terms arose mostly from BHF - trying to capture the activity of non phys small molecules

Pathways: Is limited to events within the receiving cell Begins with reception of a signal See slide for other aspects…

Is it ok to say that insulin would get the annotation response to insulin stimulus (result of relationship between insulin receptor signaling pathway being is_a cellular response to insulin stimulus)

PD: Yes it is. Even though the language is ugly

VW: wouldn't be surprised to retrieve insulin a search with this

SO: would be surprised if it didn't

AT: thinks it is misleading

BF: if pathway includes the ligand and pathway is part of the response then it makes sense

RL: can live with this one slightly weird exception - final decision

How pathways are split and named

BF: EGF receptor activity binds EGF but EGF receptor pathway is used more broadly EGF binding receptor activity

AT: end response depends on both receptor and ligand. How much further down the pathway would you go to get to the next generic cassette

BF: multiple receptors and multiple ligands a problem. FGF activated EGF receptor signaling pathway

EGF activated FGF pathway could have the child EGF binding receptor activity

Process: signal transduction (merged with pathway) EGF-activated signaling pathway EGF-activated pathway by FGFR EGF-activated pathway by EGFR EGFR signaling pathway EGF-activated pathway by EGFR FGF-activated pathway by EGFR

FGFR signaling pathway EGF-activated pathway by FGFR FGF-activated pathway by FGFR

EGF-binding receptor activity

Can we use PRO IDs?

FUNCTION: now EGF receptor activity becomes EGF-binding receptor activity

AD: toll-2 v toll-4 - need to be able to distinguish between these - lose too much specificity by lumping these together. These bind wide range of different things.

AT: would nice to be able to have a generic class too if you don't have the detailed information

AD: toll-like receptors -

TLR4 signaling pathway LPS signaling by TLR4 signaling pathway HMGR2 signaling by TLR4 signaling pathway

LPS signaling pathway LPS signaling by TLR4 signaling pathway

AI: put proposal to Chris tomorrow by Sandra and Ruth, Midori [Chris thought the suggestion looked OK and mentioned that is_a diamonds are OK]

If what determines the downstream consequences is the receptor rather than the ligand then is makes more sense to name the pathway based on the receptor than the ligand.

Intracellular cassettes

Linking up intracellular modules/ cascades to receptor signaling. Cascades are not complete pathways. These maybe associated with multiple upstream receptors.

Q. Is cascade the correct terminology for any intracellular module/cassette Q. Does there have to be amplification for it to be a cascade?

SO/ST: Yes - some people would expect amplification in this context. Would also imply multiple enzyme steps.

PI3 kinase cascade - what would be in this? Should it just be signaling via PI3 kinase? What would you annotate PI3 to?

AD: Cascade less popular than pathway in titles

VW: more common with MAP kinases that other types of signaling 'cassette'

AT: amplification occurs within the wider pathway rather than necc within the cascade itself

SO: questions reason for cassettes

VK: intracellular module? Then use cascade for the proper usages of it. SMAD pathway and MAP kinase cascade would both types of intracellular modules

VW: tor signaling pathway … do we lose anything by not trying to capture the modules?

VK: SMAD pathway activated by different things - distinguishes similar but different thing

RL: MAP kinase signaling?

PD: what do we lose - lots. 3 inputs may converge and then split out again to different intracellular pathways. Useful for toll pathways - many ligand - receptor combos result in a small set of families of routes in the downstream module

AD: Important to keep these - important for pharma. Cascade or pathway? Cascade intracellular specific?

A: can still call it a pathway

VW: MAP KKK cascade - Val has three and all are associated with different processes

AT: suggestion of naming from bottom up

SO: can of worms

PR: cascade is confusing - call them all pathways

RL: want to say a MAP kinase is associated with a map kinase cascade and also associated with insulin signaling

VW: GTPase mediated signaling… occurs in lots of pathways

PD: reasonable to make a term energy metabolism - divide into sub pathways - TCA cycle, fatty acid biosynthesis etc. Is there an analogous way to break down signaling in a general way? What is useful to distinguish?

AT: Cartridges?

AI: discuss best name cassette, subprocess, cartridge

RL: Don't do any of the options on slide 59 - would result in tiny protein groups.

The options are not equivalent -1. And 2. Wouldn't give you the same annotations.

BF: MAPKKKK, MAPKKK and MAPKK would be annotated. Should MAPK be included in this cascade? Would you annotate everything from the receptor down to MAPK?

VW: sometimes that MAPK pathway refers to the whole signaling pathway rather than just the cascade.

PD: make a very general term for stuff that happens in the cytosol and have is_a children of this woolly thing - makes it useful for annotating the less specific - bypass terms. Make sense at a subsequent meeting.

BF: do we want to say these things are downstream of a particular receptor?

PD: do we want to link things together in a causal pathway? Not generally done by GO now.

RL: keep it more general and just have stuff …

PD: doesn’t like regulates in this context because it uses a 'starvation' meaning of regulates

Leaning towards option 1. Come back to the problem of defining start and ends of the cascades.

AI: have a call for each cascade to work on the beginning and ends.

AT: cascades start with enzyme based activities rather than receptors and adaptors RL: should MAPK be in MAPK cascade? General consensus:Yes seems to make sense - in terms of annotation (AT: on the basis of insulin decision)

Cascade ends with the phosphorylation of a downstream target by MAPK. Process function links would include up to MAPK. Raf and Ras should stop at the same place. Discussed having it end at activation of MAPK but this meant that MAPK would be annotated to the MAPK cascade but the MAPK activity wouldn't have a function process link.

Receptor problems

Slide 36

Not all receptors are involved in signaling and they are a class of proteins rather than an activity. Want to make receptor activity a child of signal transduction.

Constitutive receptors don't have to bind ligand - so receptors can't be defined by binding ligands.

PD: Endocytosis very similar underlying process but you'd want to keep them separate.

LDL receptors… binds PKSC9. transport receptors involved in receptor-mediated endocytosis.

BF: is there a signaling step in receptor-mediated endocytosis so that it can happily be grouped with signaling?

AT: call LDL experts and ask them? Need to check literature.

PD: signaling receptors bind to ligands that lead to change in state in the cell

LDL - doesn't really change the state of the cells so this could be a discriminating factor.

Outstanding topics

Receptor mediated endocytosis - would you split into those that signal and those that transport? Or don't call LDL a receptor - call it a transporter instead (favoured option).

P2X receptor - should this have receptor parentage?

Ligand gated channels

Calcium mediated signaling - where does it begin?

Thursday morning

Overview of yesterday’s decisions.

AT: Signal transducer - An entity capable of signaling has been assembled

EGFR signaling pathway new terms, Becky concerned that diamonds would be created

CM: Is_a diamonds are OK

VW: Stress-activated MAPK cascades used to be called stress-activated MAPK pathways (thus are now restricted). Existing annotations are not restricted to MAPK cascade, all phosphatases that feed in are annotated to the pathway term. These ptwys are not assumed to be cassettes. 100s of annotations exist to these terms, curators need to be alerted to changes. Need to revisit annotations associated with these terms.

RL: But the pathway terms are broader, covering whole pathway

VW: Also concerned about the cell integrity ptwy also.

AT: Do you alert curators to changes? Can you freeze annotations and go back and look at them

VW: Obsoletion might be the only way

MH: stress-activated MAPK cascade - synonyms only have been added, this is the only change to this term

CM: Integrating GO signaling with pathway databases talk. Aim to make more specific GO annotations for binding annotations.

ChEBI cross links will be in go_ext next month

Simple for transport, what about signaling?

RL: Receptor recycling was not discussed yesterday in context of pathways.

CM: In Reactome, Notch signaling includes transport of Notch receptor and maturation of Notch precursor and trafficking of mature Notch receptor to plasma membrane. So GO is in conflict with Reactome, Is Reactome willing to split the Notch pathway?

SJ: There is a precedent for pathways to be split. Formation of a competent receptor and formation of ligand are two separate events that precede the main signaling pathway. Reactome should be able to accommodate this.

AT: These require different types of experiments so it’s more informative to have individual cassettes

SJ: Would probably make them subpathways of larger pathway

PD: We would have a term ‘all about Notch’ which wouldn’t necessarily correspond to anything in GO.

AT: ‘all about Notch’ would start with maturation of receptor and ligand which might happen at the same time point rather than sequential events?

PD: Yes, we could make cycles not necessarily linear processes

CM: So GO would make ‘chunk’ requests to Reactome for the GO processes

PD: Reactome made a decision to not annotate mode of transport of Notch receptor to Golgi

RL: Notch binding should be a child of protein complex binding, as Notch won’t bind the ligand unless it is in the complex.

VW: So we have to make the starts and ends of the pathway

RL: Yes, we need to work out the model and then tell Reactome that this is what we would like, to see if we can correspond

VW: When we request or use a term, we should be defining them in terms of start, end etc. as we go along

CM: Can do this via TermGenie

MH: Problem is we have a load of legacy terms

CM: could probably mine the information as a start

PD: Reactome doesn’t have a rule as to where a pathway starts.

RL: Linking Functions and Processes. If we take out initiation of signal transduction and link to signal transduction process it is implied.

MH: Another example. Some processes look like duplicates of functions, so we could use a function-process link instead.

RL: EGFR activity could be part_of the EGF receptor pathway?

CM: Yes


Slide 36.

RL: All agreed that receptor should stay as a function,

CM: Might have to give further justification. Why is it a function not a process?

VK: Researchers would expect it to be a function

AT: because it’s binding.

CM: functions are mini-process and it’s difficult to draw the line, biological intuition will be OK

RL: There are different classes of receptors, either signaling or transport

SJ: What about decoy receptors (cytokine receptors, mop up stray cytokines but don’t signal or transport), researchers would expect these to be called receptors

RL: also adhesion molecules

AT: Needs to be inclusive, otherwise people will go elsewhere

VW: Importin-alpha export receptor activity has is_a parent nuclear export signal receptor activity, not the parent receptor activity, could treat LDL receptor this way

MH: People would be surprised to find a path back to signaling

VK: would they be surprised to find a path back to receptor?

AT: the word signal is a problem, just say it binds a ligand and conveys information

VW: We don’t need a grouping term for things that are called the same

RL: who thinks we need a receptor grouping term?

AT: Could have glossary term ‘receptor’ it doesn’t need a grouping term

VW: there are lots of things called receptors that just have a binding function. Have a comment describing what people call receptors but are different things

CM: Don’t mind if there is a grouping receptor term

VW: argument for not having grouping term. Confusing for analysis to have mixed things annotated to a term.

RL: Lots of things that bind and cause a change in the cells but are not called receptors, grouping term could have lots of irrelevant proteins annotated Could have mopping-up receptor activity, transport receptor activity…

PR: What about ligand-gated ion channels, these are not receptors

AT: yes, they are called receptors

PR: Many people wouldn’t call them receptors but channels

AT: channel is a synonym for receptor

PD: the word receptor appears in many places in the MF ontology, the fix would be to have an explicit modifier preceding it, e.g. ligand-gated receptor, and also have as many synonyms as is useful. Receptor in GO currently means signaling receptor, so to avoid confusion, just put signaling in front of it.

AD: channels are subsets of receptors, not an exact synonym for receptor

PD: Nutrient/nutritional receptor would cover glucose binding and LDL binding receptors

RL: Definition for receptor activity. Parent is currently ‘signal transducer activity’. Rename to signaling receptor activity and put it as a child of molecular transducer activity.

RL: Just broaden transmembrane receptor activity definition?

ACTION: Signaling receptor activity Definition: Combining with an extracellular or intracellular signal and transmitting the signal to initiate a change in cell activity. The glossary definition for ‘signal’ needs to be linked from this (and other ‘signal’) terms. Comment for signaling receptor activity needs to have something like; “this does not refer to receptors such as transporters, “mop-up” receptors, decoy receptors, adhesion receptors, importin receptor, nutrient receptors”, to make clear that there are other types of receptors. Child of ‘molecular transducer activity’

ACTION: Also make terms for other types of receptors.

Ligand-dependent (nuclear) hormone receptor

Slide 42; Need to have both transcription regulator and receptor parentage?

VW: No need to have both parents, have just receptor parent and then annotate to transcription factor. GO:0000981 needs to have a regulation parentage

RL: Receptors bind a ligand and also activate a pathway - two functions, why is it a problem to have two parents

AT: TF activity is dependent on ligand binding, coupled binding to function

VW: To annotate TF have to make two annotations, DNA binding and TF activity, DNA binding should be in the definition of TF activity.

RL: but when you come to regulation there is a true path violation, you imply that there is regulation of DNA binding AND TF activity, but this is not necessarily the case. If you consider regulating the ligand dependent receptor, if it has more than one function parent, it might regulate ligand binding without regulating receptor activity

Ligand-dependent (nuclear) hormone receptors needs to be under GO:0003706 ligand-regulated TF activity and the definition of ligand-regulated TF activity needs to be revisited

RL: can we keep nuclear in the name?

MH: if it is a feature of what is happening

ACTION: ligand-dependent nuclear receptor activity • Current Def: A ligand-dependent receptor found in the nucleus of the cell. New Definition: Combining with a cytosolic signal and transmitting the signal from one side of the nuclear membrane to the other to regulate transcription. Need to check that all do transfer across nuclear membrane, need to add parent GO:0003706 ligand-regulated TF activity

ACTION VW: Check more generally that regulatory transcription factors are children of regulatory processes

RL: Slide 43; yes we need a receptor activity that includes the channel activity terms

Receptor mediated endocytosis

Slide 63;

ALL agree: 1) synthesis of ligand is not part of signaling, inappropriate to have receptor synthesis as part of pathway, it would be regulation of endocytosis

AD: not sure as some are activated once endocytosed

ACTION AD: look up receptors that are activated once they are endocytosed

RL: Slide 64; Receptor internalization – hopefully put this under regulation of signaling, Alex needs to check this

AD: would have ‘negative/positive regulation following receptor internalization’

RL: Slide 66; Ligand transport – don’t need to discuss this, it’s just diffusion. Negative regulation?

VK: Sequestering of ligands

RL: we agree that activated ligand that is sequestered is a negative regulation of the pathway

Calcium mediated signaling

Slide 67; Is Ca transport part of calcium signaling? Analogous to other ligands, change in available amount of Ca regulates it

AT: Can have release of intracellular calcium, store re-filling - all are regulating. Regulation of Ca is so important that some people consider it a pathway

RL: Calcium homeostasis we have as a GO term. Can say that anything involved in transport is involved in homeostasis, they should be linked.

VW: can transport terms be related to homeostasis?

Receptor signaling protein activity; GO:0005057

Slide 68; Is in MF but is actually a process Propose to obsolete this term

MH: But has lots of children, want to keep these but put them under more appropriate parents Annotations are mostly to the child terms

ACTION: Propose to obsolete Receptor signaling protein activity


Reviewing the potential annotation for proteins in the insulin receptor signaling pathway which forms the basis of the curation manual.

AT: proposed the test for whether something is directly involved in a process or not should be whether it has inputs than the pathway itself i.e. branching suggests natural breaks into new pathway or cassettes.

Q. is insulin part of the pathway?

Decision: yes, based on yesterday's decision to include insulin in the pathway it could be annotated with insulin receptor signalling pathway

ST: Drosophila has many insulin-like peptides and one receptor instead of both insulin receptor and insulin-like growth factor receptor. Should the insulin-like peptides be annotated with insulin receptor signalling pathway or insulin-like growth factor signalling pathway? What do we do about the multiple insulin like ligands?

General agreement that it may be best to have a generic parent for cases like this. MH suggested use of the word type to make it clear when we are talking about classes of molecule. Here it may be best to have an insulin-type receptor signalling pathway and have insulin-type binding rather than insulin binding.

PD: issue it that things should be grouped functionally rather than by sequence similarity. Worried about the black sheep members that are structurally similar but go off to do something else. Agreed that these should be thrown out of the grouping.

VW: have generic receptor types and reduce complexity where possible

AI: Make a general parent of IGF and insulin pathways to accommodate the fly.

Q. Do we want to create a term for 'insulin receptor agonist activity' which would be part_of insulin receptor signalling pathway?

RL: now we don't have an initiation of signalling term would a new term receptor agonist activity be an appropriate function to capture this instead?

PD: didn't someone say on a call that agonists were not natural ligands? AT: No - an agonist is anything that activates a receptor regardless of whether it is natural or not.

VK: Receptor agonist activity is the first step of the insulin receptor signalling

RL: this would required many specific child terms

What about the current receptor activator activity terms - generally agreed these should be merged with the new receptor agonist terms (if created).

AI: Make new receptor agonist terms and merge in the receptor activator terms - these will be specific children of receptor binding. These will be part_of (has_part?) the appropriate receptor signalling pathway. ! Note subsequent discussion suggests that we hold off on this AI pending further discussion.

RL's proposed structure:

Growth factor receptor binding signalling pathway EGF binding signalling pathway

has_part growth factor activity (synonym agonist)

has_part growth factor receptor agonist activity

Feel we need a relationship between function and signalling process of some kind but do we need both functions? AT: prefers the growth factor activity option and wouldn't use growth factor receptor agonist activity.

Note we already have growth factor activity with a definition that MH didn't like very much and isn't signalling centred.

AI: decide if we need both of these functions terms. Need to take into account the fact that growth factor activity already.

Qs. Where does intracellular signal transduction begin? Are the insulin receptor and IRS1 involved in 'intracellular signal transduction'?

AT: 'intracellular signal transduction begins with the dimerization of the adaptor proteins and activation of IRS1 by the receptor (check this is a true reflection of what AT said!)

Conclusion was that the receptor wasn't included in intracellular signal transduction but that IRS1 is (not completely sure if that was the decision for IRS1 - confirm someone please!).

Q. Would you annotate p85 (regulatory subunit of PI3kinase) to signal transduction or regulation of signal transduction.

General agreement - signal transduction.

Q. Would you annotate p85 to phosphtidylinositol 3- kinase cascade?

General agreement - yes

AT: suggests we contact Bart Vanhaesebroeck at Barts Cancer Institute who is an PI3kinase expert for further advice.

Q. What about GSK-3 which is a last step in the pathway - is it part of the pathway or not?

We couldn't remember what conclusion was reached about this yesterday - ask Becky since this isn't in the notes. We think that GSK3 is part of the pathway for the same logic that we agreed FOXO to be part of the pathway.

Q. Is FOXO in the pathway?

General agreed yesterday that it was.