TNF signaling (R-HSA-75893) and TNFR1-induced proapoptotic signaling (R-HSA-5357786)

[ukemi]

• Create a mouse pathway: gomodel:64e7eefa00001233

• What is the best process to map onto this?
  [GO:0008625] extrinsic apoptotic signaling pathway via death domain receptors
  [GO:0033209] tumor necrosis factor-mediated signaling pathway

• Should we flag this for Reactome review? The pathway can branch via RIP3 and has the choice of necroptosis versus apoptosis. PMID:24557836, PMID: 37415620 (nice current review).

• This is an example of where I have placed two 'cassettes' in a single model. Is this a good idea? Should I add the downstream signaling after caspase-8 activity?

• I have added an additional step into the reaction flow, which is the action of Eed on the sphingomyelin phosphodiesterase activity (PMID:20080539). In the Reactome pathway, the action of RACK1 directly affects the binding to the SMPDs. I've retained the adaptor activity of RACK1 as a suggestion, but I think if this is causally attached to the phosphodiesterase activity, it will reason to be an activator. Or would it be better to just make it an activator? It might be that in some cases it is.

• In this reaction, TNF-α:TNFR1 binds DENN/MADD (Id: R-HSA-5626953), the isoforms in the set that bind the receptor can have different effects on the pathway according to PMID:11577081. I'm going to make this reaction map to signaling receptor regulator activity, but technically this is against GO-CAM annotation practice because the regulation should be directional.

• Should 9697750 be switched from a black box to a reaction?

• This is a general question wrt the ubiquitination as well. Do we want to represent it as a process or as a reaction representing only the action of the E3 ligase? In Reactome they are black box reactions and often the complex also contains the E2 conjugating enzyme.

• Along those same lines, I find that when I make my mouse models, I sometimes insert functions of other members of a protein complex that do not 'catalyze' reactions in the Reactome pathway. In Reactome, they are just shown as members of the complex. But in GO-CAM, I think we want to put a function on every member if we can.