inappropriate placement of cytokine receptor binding terms

[gocentral]

Hi

I think I may have raised this issue before, but can't remember what I listed this under.

Basically gp130 is a subunit of several IL receptors, eg IL6, IL27 as well as non interleukin receptors such as ciliary neurotrophic factor receptor (CNTFR).

Consequently it binds to several receptor molecules as well as binding to the cytokine itself (eg it binds CNTFR, IL6R). The terms GO:0005127 ciliary neurotrophic factor receptor binding and GO:0005138 interleukin-6 receptor binding cannot be used to describe this relationship because as they stand they are both child terms of GO:0005125 cytokine activity (and the IL6 term is also a child of GO:0008083 growth factor activity.)

At the end of the day the only protein that can be associated with GO:0005127 ciliary neurotrophic factor receptor binding is CNTF itself, so as the ontology stands this is a GO term for a single gene product, which I was under the impression GO was trying to avoid.

By moving GO:0005127 ciliary neurotrophic factor receptor binding and GO:0005138 interleukin-6 receptor binding to be direct child terms of GO:0005102 receptor binding multiple proteins could be associated with these terms, including gp130 and proteins which are downstream targets of these receptors (if they bind the receptor).

The majority of the other receptors have this ligand and non-ligand binding format and consequently can be associated with multiple proteins. I would like to see this format for all cytokine and growth factor receptors. But for now moving IL6 and CNTF would be great.

Moving all the cytokine/growth factor receptor terms would mean that all the cytokines/growth factors currently associated with cytokine receptor binding terms would have to be associated with both cytokine activity and the appropriate receptor binding term.

Hope this makes sense

Ruth

Reported by: RLovering

Original Ticket: "geneontology/ontology-requests/5564":https://sourceforge.net/p/geneontology/ontology-requests/5564

[gocentral]

I have an extended comment in preparation, but the weekend calls.

-- Alex

Original comment by: addiehl

[gocentral]

Original comment by: addiehl

[gocentral]

Ruth and others,

Having thought about this issue for quite some time, I think this problem should be solved as follows:

Based on the definition of 'cytokine activity' and the definitions of its parent, 'receptor binding ; GO:0005102' as well as its child terms 'cytokine activity' simply needs to be replaced by a term, 'cytokine receptor binding activity', with the definition, 'interacting selectively with a cytokine receptor'. The 'cytokine activity' term itself should be moved as described below. In an analogous fashion to that proposed in my response to SF 2230375 and now implemented (thanks Midori), I would like to rename 'hematopoietin/interferon-class (D200-domain) cytokine receptor binding ; GO:0005126' to 'cytokine receptor binding' to be this replacement term. This would also involve moving this term to be a direct child of 'receptor binding ; GO:0005102' and making all the child of the current 'cytokine activity' to be children of this term, except for the term 'chemokine activity' (see below).

Again, I will point out that the existing GO:0005126 term is undefined, without references, and has a name based on an older and rarely used nomenclature. In modern terms, it may refer to so called 'Class II' cytokine receptors, but the cytokine receptor binding terms in the GO that refer to Class II cytokine receptors have not been placed correctly relative to this term in many cases. I suspect folks working on the GO have been mostly confused by what 'hematopoietin/interferon-class (D200-domain) cytokine receptor' really meant. So we may as well use this term as the general 'cytokine receptor binding' term.

Also, I would like to propose two additional new terms, 'chemokine receptor binding' and 'growth factor receptor binding' to be a child term of 'cytokine receptor binding'. The current children of 'growth factor activitiy' would therefore be moved to be children of 'growth factor receptor binding'. If you you at the definitions of 'cytokine activity' and 'growth factor activity' it is clear that 'growth factor activity' is a type of 'cytokine activity'. See below for additional discussion.

I have prepared a revised DAG for the cytokine and growth factor receptor binding terms, presented at the end of this comment (it's quite long). This DAG also corrects several other small errors in the placement of certain terms. Note that I have not placed all 'growth factors' under 'growth factor receptor binding' (nor some of the previously listed interleukins) as some have broader activities and so fall under the more general cytokine receptor binding. Any additional help in these placements would be appreciated. There is a graphical view of the DAG attached as a pdf file to this SF entry as well.

As for 'cytokine activity', this is a quite useful term for annotation, and one that holds immediate meaning for biologists, and thus should be retained.

Thus, based on my long-held opinion as well as discussions with David Hill, Harold Drabkin and others, I believe we should fix the placement of cytokine activity and certain other terms that deal with the intrinsic activities of particular proteins, which are are often assayed in ways that do not measure their binding to particular receptors, but rather downstream effects on biological processes. These proteins consequently act as biological signals within an organism and therefore should be children of a new term, 'extracellular signaling activity', defined as,

The intrinsic function of a gene product that is at some point in time present in an extracellular location to regulate biological processes.

DAG structure:

molecular function ; --% extracellular signaling activity ; GO:NewTerm ----% cytokine activity ; GO:0005125 ------% chemokine activity ; GO:0008009 ------% growth factor activity ; GO:0008083 ----% hormone activity ; GO:0005179 ------% adrenocorticotropin-releasing hormone activity ; GO:0017045 ------% alpha-melanocyte stimulating hormone activity ; GO:0017044 ------% digestive hormone activity ; GO:0046659 ------% diuretic hormone activity ; GO:0008613 ------% follicle-stimulating hormone activity ; GO:0016913 ------% growth hormone-releasing hormone activity ; GO:0016608 ------% luteinizing hormone-releasing factor activity ; GO:0005183 ------% melanin-concentrating hormone activity ; GO:0030354 ------% myoinhibitory hormone activity ; GO:0016085 ------% myostimulatory hormone activity ; GO:0016084 ------% neuropeptide hormone activity ; GO:0005184 --------% ecdysiostatic hormone activity ; GO:0016087 --------% ecdysis-triggering hormone activity ; GO:0008255 --------% eclosion hormone activity ; GO:0008031 --------% neurohypophyseal hormone activity ; GO:0005185 --------% prothoracicotrophic hormone activity ; GO:0018445 ------% pituitary adenylate cyclase activating polypeptide activity ; GO:0016521 ------% thyrotropin-releasing hormone activity ; GO:0008437

Of course the definition of 'extracellular signaling activity' is quite broad and subject to additional revision. Note that extracellular includes both soluble and cell-surface bound forms of cytokines, like those of the tumor necrosis family superfamily that have biological activity in their transmembrane form as well as when released from the cell surface. Putting in the 'at some point present in an extracellular location' is to acknowledge that some of these signaling molecule may act intracellularly, but all of them necessarily are found extracellularly (though sometime cellbound) at some point in their existence.

In all this rearrangement, I have artificially kept 'hormone activity' and 'cytokine activity' separate. I personally believe protein or peptide hormones are types of cytokines, but know that traditionalists and plant biologists may be upset by this assumption. One could also argue that in general cytokines act fairly locally to their point of origin, whereas hormones act globally in the body, but this is a fairly weak distinction as it is easy to find exceptions. I welcome additional discussion of this issue.

Here is the receptor binding DAG as revised by me. Note that I have omitted many non-cytokine and non-growth factor terms that are unchanged for the sake of space. I have put notes next to certain terms for extraemphasis on particular changes. There is a graphical view of the DAG attached as a pdf file to this SF entry as well.

molecular_function ; GO:0003674 --% binding ; GO:0005488 ----% protein binding ; GO:0005515 ------% receptor binding ; GO:0005102 --------% cytokine receptor binding ; GO:0005126 ----------% chemokine receptor binding ; GO:0042379 ------------% CCR chemokine receptor binding ; GO:0048020 --------------% CCR1 chemokine receptor binding ; GO:0031726 --------------% CCR10 chemokine receptor binding ; GO:0031735 --------------% CCR11 chemokine receptor binding ; GO:0031736 --------------% CCR2 chemokine receptor binding ; GO:0031727 --------------% CCR3 chemokine receptor binding ; GO:0031728 --------------% CCR4 chemokine receptor binding ; GO:0031729 --------------% CCR5 chemokine receptor binding ; GO:0031730 --------------% CCR6 chemokine receptor binding ; GO:0031731 --------------% CCR7 chemokine receptor binding ; GO:0031732 --------------% CCR8 chemokine receptor binding ; GO:0031733 --------------% CCR9 chemokine receptor binding ; GO:0031734 ------------% CXCR chemokine receptor binding ; GO:0045236 --------------% interleukin-8 receptor binding ; GO:0005153 [IL-8 is a chemokine] ----------------% CXCR1 chemokine receptor binding ; GO:0045237 [ an IL-8 receptor ] ----------------% CXCR2 chemokine receptor binding ; GO:0045238 [ another IL-8 receptor ] --------------% CXCR3 chemokine receptor binding ; GO:0048248 --------------% CXCR4 chemokine receptor binding ; GO:0031723 --------------% CXCR5 chemokine receptor binding ; GO:0031724 --------------% CXCR6 chemokine receptor binding ; GO:0031725 ------------% CX3C chemokine receptor binding ; GO:0031737 [Note term move] ------------% XCR1 chemokine receptor binding ; GO:0031738 ----------% growth factor receptor binding ; GO:NewTerm [New Term] ------------% fibroblast growth factor receptor binding ; GO:0005104 --------------% fibroblast growth factor receptor antagonist activity ; GO:0030353 --------------% type 1 fibroblast growth factor receptor binding ; GO:0005105 --------------% type 2 fibroblast growth factor receptor binding ; GO:0005111 ------------% hepatocyte growth factor receptor binding ; GO:0005171 ------------% high molecular weight B cell growth factor receptor binding ; GO:0030372 ------------% growth hormone receptor binding ; GO:0005131 ------------% epidermal growth factor receptor binding ; GO:0005154 --------------% epidermal growth factor receptor activating ligand activity ; GO:0005155 --------------% epidermal growth factor receptor inhibiting ligand activity ; GO:0005156 --------------% gurken receptor binding ; GO:0008317 ------------% platelet-derived growth factor receptor binding ; GO:0005161 ------------% glial cell line-derived neurotrophic factor receptor binding ; GO:0030116 ------------% imaginal disc growth factor activity ; GO:0008084 ----------% ciliary neurotrophic factor receptor binding ; GO:0005127 ----------% erythropoietin receptor binding ; GO:0005128 ----------% granulocyte macrophage colony-stimulating factor receptor binding ; GO:0005129 [Note term move up one level] ----------% granulocyte colony-stimulating factor receptor binding ; GO:0005130 ----------% interferon-alpha/beta receptor binding ; GO:0005132 ----------% interferon-gamma receptor binding ; GO:0005133 ----------% interleukin-10 receptor binding ; GO:0005141 ----------% interleukin-11 receptor binding ; GO:0005142 ----------% interleukin-12 receptor binding ; GO:0005143 ----------% interleukin-13 receptor binding ; GO:0005144 ----------% interleukin-14 receptor binding ; GO:0005145 ----------% interleukin-15 receptor binding ; GO:0016170 ----------% interleukin-17 receptor binding ; GO:0030367 ----------% interleukin-17E receptor binding ; GO:0030380 ----------% interleukin-2 receptor binding ; GO:0005134 ----------% interleukin-21 receptor binding ; GO:0001531 ----------% interleukin-3 receptor binding ; GO:0005135 ----------% interleukin-4 receptor binding ; GO:0005136 ----------% interleukin-5 receptor binding ; GO:0005137 ----------% interleukin-6 receptor binding ; GO:0005138 ----------% interleukin-7 receptor binding ; GO:0005139 ----------% interleukin-9 receptor binding ; GO:0005140 ----------% leukemia inhibitory factor receptor binding ; GO:0005146 ----------% oncostatin-M receptor binding ; GO:0005147 ----------% prolactin receptor binding ; GO:0005148 ----------% interleukin-1 receptor binding ; GO:0005149 ------------% interleukin-1 receptor antagonist activity ; GO:0005152 [note revised parentage] --------------% interleukin-1 Type I receptor antagonist activity ; GO:0045352 --------------% interleukin-1 Type II receptor antagonist activity ; GO:0045353 ------------% interleukin-1, Type I receptor binding ; GO:0005150 ------------% interleukin-1, Type II receptor binding ; GO:0005151 ----------% interleukin-16 receptor binding ; GO:0045514 ----------% interleukin-18 receptor binding ; GO:0045515 ----------% interleukin-19 receptor binding ; GO:0045516 ----------% interleukin-20 receptor binding ; GO:0045517 ----------% interleukin-22 receptor binding ; GO:0045518 ----------% interleukin-23 receptor binding ; GO:0045519 ----------% interleukin-24 receptor binding ; GO:0045520 ----------% interleukin-25 receptor binding ; GO:0045521 ----------% interleukin-26 receptor binding ; GO:0045522 ----------% interleukin-27 receptor binding ; GO:0045523 ----------% interleukin-28 receptor binding ; GO:0032003 ----------% interleukin-33 receptor binding ; GO:0002112 ----------% macrophage colony stimulating factor receptor binding ; GO:0005157 ----------% neurotrophin receptor binding ; GO:0005165 ------------% brain-derived neurotrophic factor receptor binding ; GO:0031546 ------------% nerve growth factor receptor binding ; GO:0005163 ------------% neurotrophin p75 receptor binding ; GO:0005166 ------------% neurotrophin TRK receptor binding ; GO:0005167 --------------% neurotrophin TRKA receptor binding ; GO:0005168 --------------% neurotrophin TRKB receptor binding ; GO:0005169 --------------% neurotrophin TRKC receptor binding ; GO:0005170 ----------% stem cell factor receptor binding ; GO:0005173 ----------% transforming growth factor beta receptor binding ; GO:0005160 [ Note term move ] ------------% type I transforming growth factor beta receptor binding ; GO:0034713 ------------% type II transforming growth factor beta receptor binding ; GO:0005114 ------------% type III transforming growth factor beta receptor binding ; GO:0034714 ----------% tumor necrosis factor receptor superfamily binding ; GO:0032813 ------------% CD27 receptor binding ; GO:0005175 ------------% CD40 receptor binding ; GO:0005174 ------------% tumor necrosis factor receptor binding ; GO:0005164 ----------% vascular endothelial growth factor receptor binding ; GO:0005172 ------------% vascular endothelial growth factor receptor 1 binding ; GO:0043183 ------------% vascular endothelial growth factor receptor 2 binding ; GO:0043184 ------------% vascular endothelial growth factor receptor 3 binding ; GO:0043185 --------% G-protein-coupled receptor binding ; GO:0001664 ----------% chemokine receptor binding ; GO:0042379 [ These terms have dual parentage] ------------% CCR chemokine receptor binding ; GO:0048020 --------------% CCR1 chemokine receptor binding ; GO:0031726 --------------% CCR10 chemokine receptor binding ; GO:0031735 --------------% CCR11 chemokine receptor binding ; GO:0031736 --------------% CCR2 chemokine receptor binding ; GO:0031727 --------------% CCR3 chemokine receptor binding ; GO:0031728 --------------% CCR4 chemokine receptor binding ; GO:0031729 --------------% CCR5 chemokine receptor binding ; GO:0031730 --------------% CCR6 chemokine receptor binding ; GO:0031731 --------------% CCR7 chemokine receptor binding ; GO:0031732 --------------% CCR8 chemokine receptor binding ; GO:0031733 --------------% CCR9 chemokine receptor binding ; GO:0031734 ------------% CXCR chemokine receptor binding ; GO:0045236 --------------% interleukin-8 receptor binding ; GO:0005153 [IL-8 is a chemokine] ----------------% CXCR1 chemokine receptor binding ; GO:0045237 [ an IL-8 receptor, IL8RA ] ----------------% CXCR2 chemokine receptor binding ; GO:0045238 [ a second IL-8 receptor, IL8RB ] --------------% CXCR3 chemokine receptor binding ; GO:0048248 --------------% CXCR4 chemokine receptor binding ; GO:0031723 --------------% CXCR5 chemokine receptor binding ; GO:0031724 --------------% CXCR6 chemokine receptor binding ; GO:0031725 ------------% XCR1 chemokine receptor binding ; GO:0031738 ------------% CX3C chemokine receptor binding ; GO:0031737 [Note term move] --------% receptor agonist activity ; GO:0048018 --------% receptor antagonist activity ; GO:0048019 ----------% chemokine receptor antagonist activity ; GO:0046817 ----------% fibroblast growth factor receptor antagonist activity ; GO:0030353 ----------% interleukin-1 receptor antagonist activity ; GO:0005152 [ Note move up 1 level ] ------------% interleukin-1 Type I receptor antagonist activity ; GO:0045352 ------------% interleukin-1 Type II receptor antagonist activity ; GO:0045353

File Added: receptor_binding_DAG.pdf

Original comment by: addiehl

[gocentral]

Alex,

Thanks for your extensive comments and suggestions. I'm happy to implement almost all of the requested changes, but I am very reluctant to include the new term 'extracellular signaling activity'. Although we can accommodate a broad definition, the 'extracellular' builds in enough localization information to make me uncomfortable -- it veers beyond the intended scope of the MF ontology.

I would suggest instead putting cytokine activity and hormone activity under signal transducer activity (GO:0004871); although that term needs to have its definition reworded (as part of Jen and David's ongoing work on signaling), I expect that the new phrasing will be suitable for cytokine and hormone activities.

m

Original comment by: mah11

[gocentral]

Midori,

It was David who suggested a new term, 'signaling activity'. He definitely did not want 'signal transducer activity' for this purpose, and based on the definition of that term, I agree with him. I added the extracellular to the phrase 'signaling activity' in anticipation of objections to the potential definition, "The intrinsic function of a gene product to regulate biological processes," for 'signaling activity' since arguably, many many gene products would fulfill that definition. We could use ""The intrinsic function of a gene product to transmit a biological signal," instead, and stick to signaling activity.

Again, I would welcome your input, Ruth's, and David's too.

Thanks,

Alex

Original comment by: addiehl

[gocentral]

Alex,

Last time I talked with David about the signaling function terms, he was inclined to keep 'signal transducer activity' and recast its definition to match the relatively new parent and sibling terms (molecular transducer activity and energy transducer activity, respectively). The new def would thus be something like "the biological transducer activity that accepts a signal and converts it to another form".

That was several months ago, though, so it's entirely possible he's changed his mind as a result of working on the signaling process terms with Jen. It was a quite informal chat, too, so we didn't touch on the question of whether the def changes would require the existing term to be made obsolete.

The important point is that the current definition of signal transducer activity is bad and slated for improvement, so as stated now it's not a good guide to whether the redefined term would be a suitable parent for cytokine activity and hormone activity. If cytokines and hormones cannot be said to convert a signal from one form to another, then there's a good reason not to put those terms under signal transducer activity.

If that's the case, however, what other types of activities besides transducers would be considered 'signaling activities'? That's the part that I haven't properly understood yet. I agree that "The intrinsic function of a gene product to regulate biological processes" is an unsatisfactory definition, because it's not at all clear how that differs from saying the gene product is involved in a process of biological regulation. If we use "The intrinsic function of a gene product to transmit a biological signal," what ways are there to transmit the signal that don't fit "accepts a signal and converts it to another form"?

midori

Original comment by: mah11

[gocentral]

Hi all

I am pleased to see that the new ontology is being developed to enable a variety of (non-hormone/cytokine) proteins to have specific receptor binding capabilities.

However, my gut feeling is that hormones and cytokines function through binding to a receptor. Therefore I would expect to see them as child terms to receptor binding (as they are now), but without the specific receptor binding children.

Could we then avoid the 'signaling activity' issue?

Alternatively could cytokine activity stay under receptor binding for now, losing all its specific-receptor binding children and then if a general 'signaling activity' term (or variant of this) is required this would be inserted between receptor binding and cytokine activity, eg:

molecular_function ; GO:0003674 --% binding ; GO:0005488 ----% protein binding ; GO:0005515 ------% receptor binding ; GO:0005102 -------% signaling activity ; GO:NewTerm --------% cytokine activity ; GO:0005125 ----------% chemokine activity ; GO:0008009 ----------% growth factor activity ; GO:0008083 --------% hormone activity ; GO:0005179

Alternatively cytokine activity and hormone activity could just stay as child terms of receptor binding.

Ruth

Original comment by: RLovering

[gocentral]

Based on the the defs, I moved the binding terms up a level. We will hold the signal activity discussion on another day.

David

Original comment by: ukemi

[gocentral]

• status: open --> closed-accepted

Original comment by: ukemi

[gocentral]

added growth factor receptor binding GO:0070851

I just noticed (when SF 2833144 pointed back to this one) that the above new term, renaming GO:0005126, and a bunch of term moves that Alex requested didn't get done. I've now done all of the moves that wouldn't be affected by the high-level signaling activity decision. I also renamed and defined GO:0005126.

m

Original comment by: mah11

[gocentral]

Thanks for sorting this out Midori

Original comment by: RLovering