NTR: [GDF15-GFRAL signaling pathway]

[sylvainpoux]

Hi GO!

Happy new year!

I would need a bunch of new signaling pathways term for the glial cell-derived neurotrophic factor receptor signaling pathways.

We should first update the definition of GO:0035860 to indicate that it constitutes a family of coreceptors and describe the signaling.

Then it would be great to create 5 children terms, one per signaling pathway. In each case, there is one GDNF ligand (GDNF, NRTN, ARTN, PSPN and GDF15) and its corresponding GDNFR coreceptor (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively).

Note that the GDF15-GFRAL aversive pathway, a very interesting signaling pathway triggerred in response to various stresses and that causes an aversive response, is under the spotlight these days because GDF15, the cytokine/hormone that triggers the signaling is the probable cause of nausea during pregnancy.

I would also need some terms for the regulation of this pathway

Thanks

Sylvain

1) Update the name and definition of GO:0035860 Name FROM: GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway to: GO:0035860 glial cell-derived neurotrophic factor receptor family signaling pathway

Definition FROM: The series of molecular signals initiated by a ligand binding to a glial cell-derived neurotrophic factor receptor. PMID:12953054 TO: The series of molecular signals initiated by a GDNF ligand (GDNF, NRTN, ARTN, PSPN OR GDF15) binding to its glial cell-derived neurotrophic factor receptor (GFRA1, GFRA2, GFRA3, GFRA4 OR GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways. PMID:12953054

1) New term Name: GDF15-GFRAL signaling pathway Category: Biological Process Definition: The series of molecular signals initiated by GDF15 binding to GFRAL coreceptor in response to stress, triggering a RET receptor-dependent aversive response, characterized by nausea, vomitting, and/or loss of appetite.

child of GO:0033554 cellular response to stress child of GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway PMID:30639358 PMID:31535977 PMID:33593916 PMID:37437602

2) New term Name: regulation of GDF15-GFRAL signaling pathway Category: Biological Process Definition: Any process that modulates the frequency, rate or extent of Kit signaling pathway. child of GDF15-GFRAL signaling pathway PMID:35177851

3) New term Name: negative regulation of GDF15-GFRAL signaling pathway Category: Biological Process Definition: Any process that stops, prevents or reduces the frequency, rate or extent of GDF15-GFRAL signaling pathway child of regulation of GDF15-GFRAL signaling pathway PMID:35177851

4) New term Name: GDNF-GFRA1 signaling pathway Category: Biological Process Definition: The series of molecular signals initiated by GDNF binding to GFRA1 coreceptor, triggering a RET receptor-dependent response that promotes the survival of many types of neurons. child of GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway PMID:31535977

5) New term Name: NRTN-GFRA2 signaling pathway Category: Biological Process Definition: The series of molecular signals initiated by NRTN binding to GFRA2 coreceptor, triggering a RET receptor-dependent response that promotes the development and maintenance of homeostasis of the central and peripheral neurons of the nervous system. child of GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway PMID:31535977

6) New term Name: ARTN-GFRA3 signaling pathway Category: Biological Process Definition: The series of molecular signals initiated by ARTN binding to GFRA3 coreceptor, triggering a RET receptor-dependent response that promotes the development and maintenance of homeostasis of the central and peripheral neurons of the nervous system. child of GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway PMID:31535977

7) New term Name: PSPN-GFRA4 signaling pathway Category: Biological Process Definition: The series of molecular signals initiated by PSPN binding to GFRA4 coreceptor, triggering a RET receptor-dependent response that promotes the survival of promotes the survival of ventral midbrain dopaminergic neurons. child of GO:0035860 glial cell-derived neurotrophic factor receptor signaling pathway PMID:9491986 PMID:11116144

[raymond91125]

It seems that the GDNF and GDNFR interactions are not necessarily one-to-one.

PMID:12953054 Figure 1B

PMID:29245123 "However, this ligand-specific binding to GFRα co-receptors at times is promiscuous with a GFL ligand capable of interacting and functionally signaling with one of other nonpreferred GFRα proteins. GDNF can also bind to GFRα2, NRTN to GFRα1, and ARTN to GFRα1 [16], [17]."

[sylvainpoux]

Hi @raymond91125 Good point. I have not found evidence of cross-regulation in recent publications I read, but I must admit that I only read a bunch of recent publications for GDNF, NRTN, ARTN and PSPN. Concerning the GF15-GFRAL, I read in detail literature and there is no evidence of cross-regulation with another coreceptor. I therefore think we can create a term for this one. For other signaling terms ( GDNF, NRTN, ARTN and PSPN), I would say that cross-regulation is frequent in signaling and that it should not prevent creating terms for the canonical pathway. Thanks Sylvain

[raymond91125]

Thanks @sylvainpoux. My concern is that whether it is necessary to go into such granularity for glial cell-derived neurotrophic factor receptor signaling pathway in the ontology, if there is essentially one shared mechanism. It's all about a GDNF ligand binding to a GDNF receptor and followed by recruiting RET. The exact interactions may be specified in annotations of specific gene products. Would that work for you?

[sylvainpoux]

Hi @raymond91125 I think it is really important in light of recent discoveries concerning GDF15. Please note that I initially only planned to request terms for GDF15-GFRAL and that I submitted the whole list of terms following discussion with Pascale. If you think it is not needed to create all these terms, please consider the GDF15-GFRAL aversive pathway. Thanks Sylvain

[raymond91125]

@sylvainpoux Thanks for the clarification. Let's add what's immediately needed for annotations. More may be added later. Please note:

1. We don't usually add "family" in the term name. The meaning is implied.
2. The signalling pathway starts at ligand/receptor binding and ends at the regulation of a cellular process such as transcription.

[raymond91125]

+[Term] +id: GO:0160144 +name: GDF15-GFRAL signaling pathway +namespace: biological_process +def: "The series of molecular signals initiated by GDF15 binding to GFRAL coreceptor, triggering RET autophosphorylation and activation, in response to stress." [PMID:30639358, PMID:31535977, PMID:33593916, PMID:37437602] +is_a: GO:0033554 ! cellular response to stress +is_a: GO:0035860 ! glial cell-derived neurotrophic factor receptor signaling pathway +property_value: term_tracker_item "https://github.com/geneontology/go-ontology/issues/26708" xsd:anyURI +created_by: rynl +creation_date: 2024-01-12T18:40:57Z + +[Term] +id: GO:0160145 +name: negative regulation of GDF15-GFRAL signaling pathway +namespace: biological_process +def: "Any process that stops, prevents or reduces the frequency, rate or extent of GDF15-GFRAL signaling pathway." [PMID:35177851] +intersection_of: GO:0065007 ! biological regulation +intersection_of: negatively_regulates GO:0160144 ! GDF15-GFRAL signaling pathway +property_value: term_tracker_item "https://github.com/geneontology/go-ontology/issues/26708" xsd:anyURI +created_by: rynl +creation_date: 2024-01-12T20:00:40Z

[pgaudet]

Hi @raymond91125

Does anything need to be done to complete and close this ticket?

[raymond91125]

I was waiting to see if there are further comments. If not, we should close this.