new relation between terms

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The term GO:0005013 'neurotrophin TRK receptor activity' seems like it should be made an is-a child of GO:0005030 'neurotrophin receptor activity', no?

-Doug

Reported by: doughowe

Original Ticket: "geneontology/ontology-requests/1610":https://sourceforge.net/p/geneontology/ontology-requests/1610

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Original comment by: jenclark

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Yes, it should. Also, the children of GO:0005013 'neurotrophin TRK receptor activity' should be renamed so that they refer to the type of neurotrophin they bind, rather than the type of receptor it is e.g. neurotrophin TRKA receptor activity -> nerve growth factor receptor. This might mean that the parent GO:0005013 'neurotrophin TRK receptor activity' becomes obsolete though.

Original comment by: jl242

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Thanks for pointing that out Jane, I'll have a look at those.

Jen

Original comment by: jenclark

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To start with i have copied neurotrophin TRK receptor activity (GO: 0005013) (as is_a), to neurotrophin receptor activity (GO:0005030).

Original comment by: jenclark

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I'm not sure that there is only one ligand for each of the trk receptors. If there isn't then renaming them for the ligand they bind could be problematic.

This pub makes it sound like each receptor can have more than one ligand depending on the environment (Annu Rev Biochem. 2003;72:609-42. Epub 2003 Mar 27.).

And here's a clip from Cell Tissue Res. 305:229-238 (2001): "While TrkC binds only one neurotrophin (NT3), TrkA binds two (NGF, NT3) and TrkB three (BDNF, NT4/5, NT3)." -Doug

Original comment by: doughowe

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I've found out what these things bind:

TRKA receptor activity -> nerve growth factor (NGF) receptor TRKB receptor activity -> brain-derived neurotrophic factor (BDNF) receptor TRKC receptor activity -> neurotrophin 3 (NT3) receptor

Original comment by: jenclark

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TRK is tyrosin-kinase

Original comment by: jenclark

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I have done this to start with:

%neurotrophin binding ; GO:0043121 -%neurotrophin receptor activity ; GO:0005030 --%neurotrophin TRK receptor activity ; GO:0005013 ---%brain-derived neurotrophic factor receptor activity ; GO:0005015 ---%nerve growth factor receptor activity ; GO:0005014 ---%neurotrophin 3 receptor activity ; GO:0005016

%brain-derived neurotrophic factor receptor activity ; GO:0005015 synonym:BDNF receptor activity synonym:neurotrophin TRKB receptor activity

%nerve growth factor receptor activity ; GO:0005014 synonym:NGF receptor activity synonym:neurotrophin TRKA receptor activity

%neurotrophin 3 receptor activity ; GO:0005016 synonym:NT3 receptor activity synonym:neurotrophin TRKC receptor activity

Original comment by: jenclark

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Hi Doug,

Sorry, I didn't get the e-mail about your message on those publications until this morning. I'll have a look at those now.

Jen

Original comment by: jenclark

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Assistance from Amelia:

> Hi Amelia, > > I've got a sourceforge thing > https://sourceforge.net/tracker/index.php? func=detail&aid=919858&group_id=36855&atid=440764 > > on some receptors called > > neurotrophin TRKA receptor activity > neurotrophin TRKB receptor activity > neurotrophin TRKC receptor activity > > Jane says I need to change them to X binding, where X is the thing
that they bind, rather than the name of the receptor as now. However,
two of them bind more than one different thing. Does that mean I have
to obsolete the terms and make new terms: > > x receptor activity > x binding > > where x is each of the three things that these bind?

What I would do is obsolete the receptor activity terms and create 'x
binding' terms, and suggest that annotations be transferred to the
appropriate 'x binding' term and the process term 'signal transduction'. What are you going to do with the 'neurotrophin TRK receptor activity' term? Have you got a def for it?

A.

Original comment by: jenclark

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Once I obsolete the terms I could just obsolete the parent too since it has no other children. Does that seem reasonable?

Jen

Original comment by: jenclark

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If nobody objects then I'll just do that next monday 3rd May.

Jen

Original comment by: jenclark

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So 'neurotrophin TRK receptor activity' = a neurotrophin receptor which also has tyrosine kinase activity, yes?

Original comment by: girlwithglasses

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So 'neurotrophin TRK receptor activity' = a neurotrophin receptor which also has tyrosine kinase activity, yes?

-yes. TRK=tropomyosin receptor kinase. So the three TRK family neurotrophin receptors are receptor tyrosine kinases, but the p75 neurotrophin receptor is not a receptor tyrosine kinase.

So I suppose annotations could be transferred to GO:0004716 receptor signaling protein tyrosine kinase activity (which is currently undefined btw) and X-binding activity where x is one of the neurotrophins.

-Doug

Original comment by: doughowe

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That sounds like a good option then. I can define GO:0004716 receptor signaling protein tyrosine kinase activity while I'm at it. I'll make a plan for what to do and then post it here.

Jen

Original comment by: jenclark

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Hi,

I found a good summary of what this does:

The receptor tyrosine kinases (RTKs) are the second major type of cell-surface receptors that we discuss in detail in this chapter (see Figure 20-3d, right). The ligands for RTKs are soluble or membrane-bound peptide/protein hormones including nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin. Binding of a ligand to this type of receptor stimulates the receptors intrinsic protein-tyrosine kinase activity, which subsequently stimulates a signal-transduction cascade leading to changes in cellular physiology and/or patterns of gene expression (see Figure 20-6). RTK signaling pathways have a wide spectrum of functions including regulation of cell proliferation and differentiation, promotion of cell survival (Section 23.8), and modulation of cellular metabolism.

Molecular cell biology ISBN 0-7167-3136-3 1

Jen

Original comment by: jenclark

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How does this seem as a definition?

receptor signaling protein tyrosine kinase activity ; GO:0004716 def: Catalysis of the reaction: ATP + a protein tyrosine = ADP + protein tyrosine phosphate in response to the binding of a ligand.

Also can I ask another question?

Why is it that this term has general dbxref EC:2.7.1.- when it's parent protein-tyrosine kinase activity ; GO:0004713 has general dbxref 2.7.1.112

Isn't it usual that the parent of EC:2.7.1.- should be EC:2.7.-.-? I can't get EC:2.7.1.- to show up on the EC website but I'll keep trying.

Thanks,

Jen

Original comment by: jenclark

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I don't think that GO:0004716 is a true GO function - see Becky's SF item (896523) on it.

GO:0004716 is really a more specific version of GO:0004713, but if it had the same EC ref as GO:0004713, we would be saying that two GO terms were the same as EC:2.7.1.112, which would imply that the GO terms were the same. There is no way of expressing in an EC dbxref that a GO term is more specific than an EC ref, so we have to just say that GO:0004716 has activity characteristic of enzymes in the EC:2.7.1.- category.

Original comment by: girlwithglasses

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Def sounds okay. The page for EC:2.7.1.- is here:

http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/1/

Original comment by: jl242

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Hi,

I've had a look at Becky's sourceforge item and it sounds as if I'd be as well to find out if this term is being obsoleted before I make a decision on this. I'll write and ask Becky if she could have a look at this page.

Jen

Original comment by: jenclark

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I thought receptor signaling molecules were not the receptors themselves, but the proteins that signal downstream of the receptor (eg the MAPKs, JNKs etc). So I don't think any receptor function terms should have receptor signaling protein activity as a parent.

I would still like to see 'receptor signaling protein tyrosine kinase activity' and it's siblings obsoleted- I think they are very ambiguous (and hence undefined) and combine function and process terms (being a tyrosine kinase and acting in a receptor signaling pathway). So I'd prefer not to add any more children to this section.

Becky

Original comment by: beckyfoulger

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Hi,

How would this seem as a plan then? It follows Amelia's suggestion below.

New terms:

%neurotrophin binding ; GO:0043121 -%brain-derived neurotrophic factor binding ; synonym: BDNF binding ; GO:new -%neurotrophin-3 binding ; synonym: NT-3 ; GO:new -%neurotrophin-4/5 binding ; synonym: NT-4/5 binding ; GO:new -%nerve growth factor binding ; synonym: NGF binding ; GO:new -%platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new -%fibroblast growth factor binding ; GO:0017134 -%epidermal growth factor binding ; synonym: EGF binding ; GO:new

brain-derived neurotrophic factor binding ; BDNF binding ; GO:new def: Interacting selectively with Brain-Derived Neurotrophic Factor.

neurotrophin-3 binding ; synonym: NT-3 ; GO:new def: Interacting selectively with neurotrophin-3.

neurotrophin-4/5 binding ; synonym: NT-4/5 binding ; GO:new def: Interacting selectively with neurotrophin-4/5.

nerve growth factor binding ; synonym: NGF binding ; GO:new def: Interacting selectively with nerve growth factor.

platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new def: Interacting selectively with platelet-derived growth factor.

fibroblast growth factor binding ; GO:0017134 Interacting selectively with intracellular fibroblast growth factor.

epidermal growth factor binding ; synonym: EGF binding ; GO:new def: Interacting selectively with epidermal growth factor.

Obsolete terms:

neurotrophin TRKA receptor activity ; GO:0005014 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function terms 'neurotrophin-3 binding ; GO:new' and 'nerve growth factor binding ; GO:new', and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRKB receptor activity ; GO:0005015 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function terms 'neurotrophin-3 binding ; GO:new', 'neurotrophin-4/5 binding ; GO:new' and 'Brain-Derived Neurotrophic Factor binding ; GO:new'; and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRKC receptor activity ; GO:0005016 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function term 'neurotrophin-3 binding ; GO:new', and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRK receptor activity ; GO:0005013 obsolete with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function terms that are children of 'neurotrophin binding ; GO:0043121', and the biological process term 'signal transduction ; GO:0007165'.

Jen

Original comment by: jenclark

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A few things:

• you don't need the capitalization in brain-derived neurotrophic factor.
• does neurotrophin-4/5 represent a complex of nt-4 and nt-5?
• why does the FGF def have 'intracellular' in it?
• what's happened about the RTK stuff?

Original comment by: girlwithglasses

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Hi,

- does neurotrophin-4/5 represent a complex of nt-4 and nt-5?

nt-4 and nt-5 seem to be homolgues. I've found nothing to suggest that they dimerise or anything so I think the idea must be that the two are interchangeable.

J Neurosci Res. 1992 Aug;32(4):461-70. Related Articles, Links Function and evolution in the NGF family and its receptors. Ebendal T. PMID: 1326636 http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi? cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1326636

Jen

Original comment by: jenclark

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- why does the FGF def have 'intracellular' in it?

I'm not sure, I didn't write that. It's a term that already exists in the ontology.

Jen

Original comment by: jenclark

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re: nt-4/nt-5 - if 'nt-4/nt-5' doesn't represent a complex, I would make separate terms for binding nt-4 and nt-5.

Original comment by: girlwithglasses

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Rightio. I'd quite like to give them both some kind of synonym of nt-4/5 though since that's what they're called in the literture.

Doug, would you agree with this interpretation of nt-4/5?

Jen

Original comment by: jenclark

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- what's happened about the RTK stuff?

I think the RTKs are another name for the TRK receptor mentioned in the name of the terms I'm going to obsolete. Is that what you mean?

Jen

Original comment by: jenclark

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A quick search of LocusLink suggests that nt4 is an alternate symbol for nt5. This leads me to think that nt4 and nt5 represent the same entity, and thus should remain as a single unit named nt4/5 as it is used in the literature. This might be a good specific question to be clarified by an expert on the neurotrophins.

Original comment by: doughowe

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I might add that LocusLink also does not have an entity named NT4 for human or mouse, only NT5 using NT4 as an alternate name. It appears that there was a time when people thought there was an entity NT4, but have come to realize it is actually NT5...so it has this dual existence now as NT4/5. I believe the "proper" name for it now is NT5, and we could have a synonym that uses the 4/5 nomenclature? Again, I think it would be worth bouncing this off an expert in the field to get their spin.

-Doug

Original comment by: doughowe

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Hi Doug,

Thanks for explaining. That makes perfect sense according to the stuff I've read. I'm sure there will be someone around here who knows about this and can confirm. I'll ask around.

Thanks,

Jen

Original comment by: jenclark

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Hi Doug,

One of the other curators here told me this:

The HUGO name for neurotrophin-4/5 is neurotrophin-5 with neurotrophin-4/5 listed as a synonym (http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/get\_data.pl? hgnc_id=8024).

And the following is taken from the OMIM entry for neurotrophin-5 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162662):

"Nomenclature: Neurotrophin-5 (NTF5 or NT5) has been also referred to as neurotrophin-4 (NTF4 or NT4). Ibanez (1996) noted that confusion over the nomenclature of this factor arose because this mammalian neurotrophin is much more divergent from its amphibian counterpart (NT4) than are the other members of the family; hence the designation 'neurotrophin-5.' Subsequent studies demonstrated a functional correspondence between this protein and the amphibian NT4 protein. Some laboratories adopted the nomenclature 'neurotrophin-4/5' to denote the mammalian counterpart of Xenopus NT4."

Jen

Original comment by: jenclark

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If neurotrophin-4 and neurotrophin-5 have been shown to correspond in function then they don't need sparate terms as far as I can see. The most common name I've come across is neurotrophin-4/5 so could we use that for the term name and we could also have synonyms of neurotrophin-4 and neurotrophin-5. Does that seem reasonable?

Jen

Original comment by: jenclark

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This sounds reasonable to me. It is likely people will search for NT4 or NT5 as well, so these should be used as synonyms in addition to the full terms. Thanks for your hard work on these sometimes convoluted issues!!

Original comment by: doughowe

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Perhaps you can say something in the def to explain about nt-4/nt-5?

The RTK thing I was asking about several comments ago was to do with the suggested alternative terms. ATM, you've got:

neurotrophin TRKA receptor activity ; GO:0005014 To update annotations, consider the molecular function terms 'neurotrophin-3 binding ; GO:new' and 'nerve growth factor binding ; GO:new', and the biological process term 'signal transduction ; GO:0007165'.

You've got the neurotrophin receptor bit covered, but there's nothing about the TRK (tropomyosin receptor kinase) activity. Is this pending the results of Becky's investigations? Otherwise, maybe 'protein-tyrosine kinase activity ; GO:0004713' would be an option.

Original comment by: girlwithglasses

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To cover the TRK part, why not use GO:0004714 'transmembrane receptor protein tyrosine kinase activity', rather than "protein tyrosine kinase activity"? As far as I know all the receptors under consideration here are transmembrane proteins.

Also, The last proposed structure posted by Jen looked like this: New terms:

%neurotrophin binding ; GO:0043121 -%brain-derived neurotrophic factor binding ; synonym: BDNF binding ; GO:new -%neurotrophin-3 binding ; synonym: NT-3 ; GO:new -%neurotrophin-4/5 binding ; synonym: NT-4/5 binding ; GO:new -%nerve growth factor binding ; synonym: NGF binding ; GO:new -%platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new -%fibroblast growth factor binding ; GO:0017134 -%epidermal growth factor binding ; synonym: EGF binding ; GO:new

In that proposed structure, I don't think FGF, PDGF or EGF are considered to be neurotrophins, so they should be moved out to come under growth factor binding (GO:0019838). FGF binding is already in this correct position.

I think we are closing in on it now!!

Original comment by: doughowe

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Hi,

Here's the improved version:

New terms: %growth factor binding ; GO:0019838 -%neurotrophin binding ; GO:0043121 --%brain-derived neurotrophic factor binding ; synonym: BDNF binding ; GO:new --%neurotrophin-3 binding ; synonym: NT-3 ; GO:new --%neurotrophin-4/5 binding ; synonym: NT-4 binding ; synonym: NT-5 binding ; synonym: NT-4/5 binding ; GO:new --%nerve growth factor binding ; synonym: NGF binding ; GO:new -%platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new -%fibroblast growth factor binding ; GO:0017134 -%epidermal growth factor binding ; synonym: EGF binding ; GO:new

brain-derived neurotrophic factor binding ; BDNF binding ; GO:new def: Interacting selectively with brain-derived neurotrophic factor.

neurotrophin-3 binding ; synonym: NT-3 ; GO:new def: Interacting selectively with neurotrophin-3.

neurotrophin-4/5 binding ; GO:new synonym: NT-4 binding ; synonym: NT-5 binding ; synonym: NT-4/5 binding ; GO:new def: Interacting selectively with neurotrophin-4/5 Comment: Mammalian NT-5 was initially named differently from amphibian NT-4 because of sequence differences, but the two genes were later shown to be functionally equivalent [SF919858].

nerve growth factor binding ; synonym: NGF binding ; GO:new def: Interacting selectively with nerve growth factor.

platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new def: Interacting selectively with platelet-derived growth factor.

fibroblast growth factor binding ; GO:0017134 Interacting selectively with intracellular fibroblast growth factor.

epidermal growth factor binding ; synonym: EGF binding ; GO:new def: Interacting selectively with epidermal growth factor.

Obsolete terms:

neurotrophin TRKA receptor activity ; GO:0005014 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function terms 'transmembrane receptor protein tyrosine kinase activity ; GO:0004714', 'neurotrophin-3 binding ; GO:new' and 'nerve growth factor binding ; GO:new', and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRKB receptor activity ; GO:0005015 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function terms 'transmembrane receptor protein tyrosine kinase activity ; GO:0004714', 'neurotrophin-3 binding ; GO:new', 'neurotrophin-4/5 binding ; GO:new' and 'Brain-Derived Neurotrophic Factor binding ; GO:new'; and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRKC receptor activity ; GO:0005016 with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function term 'transmembrane receptor protein tyrosine kinase activity ; GO:0004714', 'neurotrophin-3 binding ; GO:new', and the biological process term 'signal transduction ; GO:0007165'.

neurotrophin TRK receptor activity ; GO:0005013 obsolete with comment: This term was made obsolete because it represents a gene product. To update annotations, consider the molecular function term 'transmembrane receptor protein tyrosine kinase activity ; GO:0004714', those that are children of 'neurotrophin binding ; GO:0043121' and growth factor binding ; GO:0019838, and the biological process term 'signal transduction ; GO:0007165'.

I notice that in the literature NT-3 nearly always but not quite always has a hyphen, NT-4 NT-5 vary and NT 4/5 hardly ever has a hyphen. Shall I standardize to having a hyphen?

Jen

Original comment by: jenclark

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I think it looks dahsing! A couple of small corrections i the following part:

-%platelet-derived growth factor binding ; syonym: PDGF binding ; GO:new

the word synonym is misspelled in the above...This probably wouldn't get into the actual ontology..but better safe than sorry!

fibroblast growth factor should have an exact synonym of PDGF.

With respect to the use of a "-" in the names, like NT-3, I am fine with standardizing to using a dash in the name (NT-3 for example) and providing a non-dash name (NT3 for example) as a synonym.

-Doug

Original comment by: doughowe

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Excellent. :-) I think we're about ready to go then. Amelia's away giving a GO course all week. We should probably hang on until she can have a look at this at the beginning of next week but I can implement it straight after that if she's happy with it too.

Thanks,

Jen

Original comment by: jenclark

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Yep, this seems OK now. Go for it!

Original comment by: girlwithglasses

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Excellent! Thanks :-)

Jen

Original comment by: jenclark

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Hi,

I have implemented this now.

The new terms have the following numbers:

GO:0048403 brain-derived neurotrophic factor binding GO:0048404 neurotrophin-3 binding GO:0048405 neurotrophin-4/5 binding GO:0048406 nerve growth factor binding GO:0048407 platelet-derived growth factor binding GO:0048408 epidermal growth factor binding

I put myself as dbxref for the obsolete terms and Doug as the dbxref for the new terms, but is that right? I'm not if Doug should go in as dbxref for the obsoletes too.

Thanks,

Jen

Original comment by: jenclark

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One note...

It must have been the end of a long week when I said:

"fibroblast growth factor should have an exact synonym of PDGF."

If THAT didn't confuse anyone...well then....

fibroblast growth factor SHOULD have an exact synonym of FGF.

Hopefully that little slip-up didn't make it through!

Regarding the dbxrefs...I'd say this was a team effort...but if you would rather have me as the dbxref for the obsoletes...thats OK with me as well since I started this whole mess!

-Doug

Original comment by: doughowe

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Hi Doug,

Thanks for pointing that out. :-) I'll fix that synonym and then close this. :-) Thanks for all your help with working this all out.

Jen

Original comment by: jenclark

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• milestone: --> TermGenie
• status: open --> closed-fixed

Original comment by: jenclark