MAPK cascade- Signaling Project

[ukemi]

Google spreadsheet of annotations to genes annotated to the MAPK cascade:https://docs.google.com/spreadsheets/d/198q2DtHRmzbXa9icUIu30DoaRjwKKQkCROfE1KsoO6I/edit#gid=1361703775

• review annotations to the MAPK cascade

• Flag annotations that are annotated to the cascade but do not have MF support as being part of the process.

• check term and annotations to GO:0000189 'MAPK import into nucleus'. It is currently part of the MAPK cascade. general question about localization/transport within a signalling pathway - MAPK import into nucleus #1596

• GO-CAM models are here: http://noctua.berkeleybop.org/editor/graph/gomodel:5437882f00000024 http://noctua.berkeleybop.org/editor/graph/gomodel:5966411600000155

• check term and annotations to GO:0005078 'MAP-kinase scaffold activity'. How does this molecular function relate to the cascade?

• How do we identify the specific MAPK pathways.
  Pombe has 3 regulating conjugation, stress (sometimes known as osmolarity signalling). These have over time found their way into GO. It is difficult to see this working for all species. How to name specific MAPK pathways #1597

• Is a "MAPK activated kinase" part of the MAPK cascade? Is a MAPK activated kinase part of the MAPK cascade? #1598 This needs to be discussed.

• How do name the specific MAPK pathways.
  How to name specific MAPK pathways go-ontology#14676

[ValWood]

This is the "PomCam" (automatically generated from GO annotation) model of the 3
MAP kinase pathways today.
If you connect the MF's up correctly, the models resolve themselves without requiring Noctua

Our next step for the network generating work is to have more labelling so that you can see what the actual gene products, activities and relations are...

[RLovering]

Can you colour the nodes according to annotation to a specific GO pathway?

[ValWood]

Hi @RLovering I put some notes on this in a ticket if you are interested pombase/curation#1699

Can answer questions at the meeting...

[hattrill]

Hi @ukemi @sabrinatoro
I know there was discussion on the role of MAPK scaffolding proteins at the GOC meeting, but I am not sure if any firm conclusion was reached wrt regulation vs within pathway.
Can you advise?
Thanks.

[ValWood]

I think the conclusion was, that @ukemi thinks they are regulators and I don't ;) ...I think they are part of pathway, because they are effectively a 'complex' with the MAPK'/K/Ks.

They prevent "incorrect signal flow" it prevents cross-talk signaling but I'm not convinced that they regulate pathway choice.... because the complex exists before the pathway is 'activated'.

.....But, I'm happy to annotate them as "regulators" if that is the consensus.

[hattrill]

Hmmm.....then there is only one way to decide - an arm wrestling contest!

[hattrill]

Just to completely trash this ticket with side-issues - did anyone define where Ras signaling ends? I have annotations to ksr to Ras protein signal transduction. This applies to older papers when the assays are essentially looking at genetic interactions. Before I move them and get UniProt to chip in, I'd like to be sure.

[sabrinatoro]

Based on the publications, the scaffold protein is necessary to bring the MAPKinases together. You can look at it as a protein which assemble the complex, but is not really part of that complex. David and I agreed that it regulates the pathway. (I am not sure what the 'latest' correct relation is: directly_activates, or directly positively regulates,...)
However, it is GO, so we can review the publications and discuss this during one of our calls...

[ValWood]

Hmmm.....then there is only one way to decide - an arm wrestling contest!

I'll put that down for the Cambridge Montreal meeting...

[ValWood]

but is not really part of that complex.

I thought it was...why is that?

[ValWood]

OK I just found this.

Abstract
The scaffold proteins of signaling pathways are thought to act as passive tethering devices bringing together catalytic components of signaling cascades. Good et al. (2009) now reveal that in the budding yeast the scaffold protein Ste5 acts as an allosteric activator of the mitogen-activated protein kinase Fus3, rendering it competent to be a kinase substrate for signal transmission.

Comment on
The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation. [Cell. 2009]
PMID: 19303841

So in this case it is regulating the pathway.
But passive tethering devices/scaffolds are not generally "regulators".

This would need a separate annotation IMHO
under "enzyme regulator activity". It isn't a scaffold activity.....

[ukemi]

There are other cases/experiments like this one.

[ValWood]

My expert thinks it is "part of the pathway":

I would argue that it is a bit of both. It is a physical component of the pathway, thus a.

It is and is not an upstream regulator. The scaffold holds the various kinases (KKK, KK and K) together into a signaling complex. Loss of the scaffold would therefore lead to loss of signaling.

Is it upstream? Yes, in the a mutation that activates a MAPK would suppress the loss of the scaffold.
No, in that a mutation that activates the MAPKKK or MAPKK would not suppress the loss of the scaffold, since you would still have a defect in signaling to the MAPK.

Charlie

On Thu, May 31, 2018 at 11:50 AM, Valerie Wood vw253@cam.ac.uk wrote:

A quick  (hopefully) question.

Is a MAPK scaffold

a) 'part' of the MAPK signaling pathway

b)  an 'upstream regulator' of a MAPK signalling pathway?

Val

[ValWood]

So here is my take on this.

1. The scaffold is part of the pathway.

2. The scaffold has another function as an direct upstream regulator (always or sometimes?).

I would have annotated for the example above

1. MAPK scaffold activity part_of MAPK signalling pathway has_input MAPKKK, MAPKK,MAPK

AND

2. enzyme regulator activity (or more specific child) has_direct_input MAPK (In the above eg) part_of MAPK signalling pathway
   (because here, it is acting as a canonical allosteric activator and this is separable from its scaffold activity)

[hattrill]

That's a good point about the enzyme reg function, as it certainly isn't just a passive scaffold.
I think that for now I will go with "part of", to distinguish it from casual (not causal!) interlopers that modulate the cascade.
(But happy to yield)

[pgaudet]

Looks like the suggestions here were all implemented. MAPK annotations have been reviewed for the 2023/2024 signaling cascade project:
#4930
#4929
#4928
#4865

[pfey03]

@ukemi
is it GO:0000165 MAPK cascade? I'm agains obsoleting this term.
Explain exactly what terms are obsoleted? or in discussion?
OK, when I see the tickets linked from @pgaudet then I'm not concerned

[pgaudet]

To clarify: GO:0000165 MAPK cascade is not being obsoleted

[pfey03]

Thanks @pgaudet