Cascades: Difference between revisions

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Pablo needs some [http://en.wikipedia.org/wiki/NF-%CE%BAB NF-KappaB] terms for apoptosis, which has highlighted some problems with the 'I-kappaB kinase/NF-kappaB cascade ; GO:0007249' terms.  
Pablo needs some [http://en.wikipedia.org/wiki/NF-%CE%BAB NF-KappaB] terms for apoptosis, which has highlighted some problems with the 'I-kappaB kinase/NF-kappaB cascade ; GO:0007249' terms.  
As of October 2011, the node looked like this:


[[File:Screen_shot_2011-10-21_at_11.07.54.png]]
[[File:Screen_shot_2011-10-21_at_11.07.54.png]]


A summary of the signaling events:
A summary of the signaling events:
Line 79: Line 82:
# NF-KB dimers are subject to futher PTMs to regulate them.
# NF-KB dimers are subject to futher PTMs to regulate them.
# NF-KB dimers bind to promoter/enhancer regions in DNA to enhance/repress transcription.
# NF-KB dimers bind to promoter/enhancer regions in DNA to enhance/repress transcription.


==NFKAPPA-B EDITS SPRING 2012==
==NFKAPPA-B EDITS SPRING 2012==

Revision as of 08:42, 30 May 2012

Return to GOC Main Page

Return to Signaling Main Page [[1]]


Connecting Intracellular Cascades To Cell Surface Receptors

  • For the problems of connecting the intracellular signaling cascades with the cell surface receptors above them, see slides 26-32 of the overview from the LA GOC meeting, May 2011.
  • From the GO signaling workshop and the LA 2011 GO meeting, it was agreed that 'VIA' (and HAS_PART relationships) was the most appropriate syntax for these terms.
  • For the current discussions on representing the regulatory nature of signaling pathways, see [2]



EDITS: SEPTEMBER 8th 2011

OBSOLETED:
intracellular signal transduction involved in cell surface receptor linked signaling ; GO:0035557
phosphatidylinositol 3-kinase cascade involved in insulin receptor signaling ; GO:0035558
MAPKKK cascade involved in epidermal growth factor receptor signaling ; GO:0035559 


Created new Replacement Terms:

id: GO:0038028
name: insulin receptor signaling pathway via phosphatidylinositol 3-kinase cascade
namespace: biological_process
def: "The series of molecular signals generated as a consequence of the insulin receptor binding to its physiological ligand, where the signal is passed on via the   phosphatidylinositol 3-kinase cascade." [GOC:bf, GOC:signaling, PMID:19322168, PMID:20696212]
synonym: "insulin receptor signaling pathway via PI3K cascade" EXACT [GOC:bf]
synonym: "insulin receptor signaling via PI3K" EXACT [GOC:bf]
is_a: GO:0008286 ! insulin receptor signaling pathway
relationship: has_part GO:0014065 ! phosphatidylinositol 3-kinase cascade
id: GO:0038029
name: epidermal growth factor receptor signaling pathway via MAPKKK cascade
namespace: biological_process
def: "The series of molecular signals generated as a consequence of an epidermal growth factor receptor binding to one of its physiological ligands, where the signal is  passed on via the MAPKKK cascade." [GOC:bf, GOC:signaling, PMID:21167805]
synonym: "EGFR signaling pathway via MAPKKK cascade" EXACT [GOC:bf]
synonym: "EGFR signaling via MAPKKK cascade" EXACT [GOC:bf]
synonym: "EGFR/MAPK signaling" EXACT [GOC:bf]
synonym: "epidermal growth factor receptor signalling pathway via MAPKKK cascade" EXACT [GOC:bf]
is_a: GO:0007173 ! epidermal growth factor receptor signaling pathway
relationship: has_part GO:0000165 ! MAPKKK cascade
For SF:3023417, created:
non-canonical Wnt receptor signaling pathway via MAPKKK cascade ; GO:0038030
non-canonical Wnt receptor signaling pathway via JNK cascade ; GO:0038031


Related SourceForge Items



NF-KappaB

Pablo needs some NF-KappaB terms for apoptosis, which has highlighted some problems with the 'I-kappaB kinase/NF-kappaB cascade ; GO:0007249' terms.

As of October 2011, the node looked like this:


A summary of the signaling events:


  1. In resting phase, NF-KB dimers are bound to inhibitory IKB proteins, sequestering NF-KB in the cytoplasm.
  2. IKK is activated by signaling from upstream receptors and intracellular signaling proteins (E.g. TRAFs)
  3. IKK (IKB kinase complex, consisting of IKKalpha (kinase), IKKbeta (kinase) and IKKgamma (regulatory) subunits) phosphorylates IKB.
  4. Phosphorylated IKB proteins are targeted for ubiquitination and degradation.
  5. Degradation of IKB releases the NF-KB dimers, which translocate to the nucleus.
  6. NF-KB dimers are subject to futher PTMs to regulate them.
  7. NF-KB dimers bind to promoter/enhancer regions in DNA to enhance/repress transcription.

NFKAPPA-B EDITS SPRING 2012

  • In talks with Reactome, created a new signaling pathway to represent an alternative route of NF-KB activation:
NIK/NF-kappaB cascade ; GO:0038061
The process in which a signal is passed on to downstream components within the cell through the NIK-dependent processing and activation of NF-KappaB. The cascade begins with activation of the NF-KappaB-inducing kinase (NIK), which in turn phosphorylates and activates IkappaB kinase alpha (IKKalpha). IKKalpha phosphorylates the NF-Kappa B2 protein (p100) leading to p100 processing and release of an active NF-KappaB (p52).

Gave it the relationship: HAS_PART: positive regulation of NF-kappaB transcription factor activity ; GO:0051092

  • Redefined I-kappaB kinase/NF-kappaB cascade ; GO:0007249
I-kappaB kinase/NF-kappaB cascade ; GO:0007249
The process in which a signal is passed on to downstream components within the cell through the I-kappaB-kinase (IKK)-dependent activation of NF-kappaB. The cascade begins with activation of a trimeric IKK complex (consisting of catalytic kinase subunits IKKalpha and/or IKKbeta, and the regulatory scaffold protein NEMO) and ends with the regulation of transcription of target genes by NF-kappaB. In a resting state, NF-kappaB dimers are bound to I-kappaB proteins, sequestering NF-kappaB in the cytoplasm. Phosphorylation of I-kappaB targets I-kappaB for ubiquitination and proteasomal degradation, thus releasing the NF-kappaB dimers, which can translocate to the nucleus to bind DNA and regulate transcription.
  • Rejigged the children of both cascades, so that as of May 2012 the node looks like this:





Previous Questions We Tried To Answer:

  • What does the cascade cover? Most steps in the current cascade (eg 'cytoplasmic sequestering of NF-kappaB ; GO:0007253') prevent the signal from being passed on.
  • Would it be better renamed as NF-KappaB signaling, with positive and negative regulation terms?
  • If we rename it to NF-KappaB signaling, where does this start? If it starts with a released NF-KappaB, there's not many steps to it.

See PMID 21772278 for an overview, useful figures etc.

Naming The Cascades

For the problems of connecting the intracellular signaling cascades with the cell surface receptors above them, see slide 32 of the overview from the LA GOC meeting, May 2011.

IN SUMMARY:

  • There was a concern that ‘cascade’ implied amplification of a signal.
  • The SWG and experts discussed various options including 'cascade, cassette, module'.
  • It was decided to stick with 'cascade' in GO, and making it clear in the definitions that amplification of a signal was not required.



Cascade Problems Still To Address

Q: Where does a cascade start and stop?


Intracellular signaling units can be split into those that are a group of proteins:

  • MAPKKK cascade
  • JNK cascade
  • Hippo cascade

and those that are really just one mediator/protein:

  • PI3K
  • PKB (aka AKT) (NB: PI3K and AKT NORMALLY (but not always) signal together so we need to look at how we can connect them.
  • TOR
  • Ca++ signaling
  • Activation/inhibition of adenylate cyclase in GPCR signaling

For those that are just one mediator, it's harder to define a start and stop point. Where, for example, does the PI3K cascade begin and end? For these, it may be easier to rename them to 'PI3K signaling'. If we keep it as an instance of intracellular signal transduction, it can be defined as any signaling event within the cell where PI3K passes the signal on.