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A Database of human biological pathways Bijay Jassal. Rationale – Journal information. Nature 407(6805):770-6.The Biochemistry of Apoptosis.

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Rationale journal information
Rationale – Journal information

Nature 407(6805):770-6.The Biochemistry of Apoptosis.

“Caspase-8 is the key initiator caspase in the death-receptor pathway. Upon ligand binding, death receptors such as CD95 (Apo-1/Fas) aggregate and form membrane-bound signalling complexes (Box 3). These complexes then recruit, through adapter proteins, several molecules of procaspase-8, resulting in a high local concentration of zymogen. The induced proximity model posits that under these crowded conditions, the low intrinsic protease activity of procaspase-8 (ref. 20) is sufficient to allow the various proenzyme molecules to mutually cleave and activate each other (Box 2). A similar mechanism of action has been proposed to mediate the activation of several other caspases, including caspase-2 and the nematode caspase CED-3 (ref. 21).”

How can I access the pathway described here and maybe reuse it?


Rationale figures
Rationale - Figures

A picture paints a thousand words…

  • but….

  • Just pixels

  • Omits key details

  • Assumes

  • Fact or Hypothesis?

Nature. 2000 Oct 12;407(6805):770-6.

The biochemistry of apoptosis.


Reactome is
Reactome is…

Free, online, open-source curated

database of pathways and reactions in human biology

Authored by expert biologists, maintained by

Reactome editorial staff (curators)

Mapped to cellular compartment


Reactome is1
Reactome is…

Extensively cross-referenced

Tools for data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart…

Used to infer orthologous events in 20 non-human species


Theory reactions

BINDING

DEGRADATION

DISSOCIATION

DEPHOSPHORYLATION

PHOSPHORYLATION

CLASSIC

BIOCHEMICAL

TRANSPORT

Theory - Reactions

Pathway steps = the “units” of Reactome

= events in biology



Reaction example 2 transport
Reaction Example 2: Transport

Transport of Ca++ from platelet dense tubular system to cytoplasm

REACT_945.4


Other reaction types
Other Reaction Types

Dimerization

Binding

Phosphorylation


Reactions connect into pathways
Reactions Connect into Pathways

CATALYST

CATALYST

CATALYST

INPUT

OUTPUT

INPUT

OUTPUT

OUTPUT

INPUT


Evidence tracking inferred reactions
Evidence Tracking – Inferred Reactions

Direct evidence

PMID:5555

PMID:4444

Human pathway

Indirect evidence

PMID:8976

mouse

PMID:1234

cow


Data expansion link outs from reactome
Data Expansion - Link-outs From Reactome

GO

Molecular Function

Compartment

Biological process

KEGG, ChEBI – small molecules

UniProt – proteins

Sequence dbs – Ensembl, OMIM, Entrez Gene, RefSeq, HapMap, UCSC, KEGG Gene

PubMed references – literature evidence for events



Data expansion projecting to other species
Data Expansion – Projecting to Other Species

Human

B

A

A

+ ATP

-P

+ ADP

Mouse

B

A

A

+ ATP

+ ADP

-P

Drosophila

Reaction not

inferred

B

+ ATP

A

No orthologue - Protein not inferred


Exportable Protein-Protein Interactions

Inferred from complexes and reactions

Interactions between proteins in the same complex, reaction, or adjoining reaction

Lists available from Downloads

See Readme document for more details


Coverage current toc
Coverage – Current TOC

And many more...



Reactome tools
Reactome Tools

Interactive Pathway Browser

Pathway Mapping and Over-representation

Expression overlay onto pathways

Molecular Interaction overlay

Biomart


Arabidopsis reactome
Arabidopsis Reactome

http://www.arabidopsisreactome.org/



Front page
Front Page

http://www.reactome.org

Navigation bar

Sidebar

Main text



The pathway browser

Search & Analyze bar

Zoom/move toolbar

Thumbnail

Species selector

The Pathway Browser

Sidebar

Pathway Diagram Panel

Details Panel (hidden)


Pathways tab pathway hierarchy
Pathways tab – pathway hierarchy

Pathway

Reaction

Black-box


Exercise 2
Exercise 2

From the homepage, search for ‘Notch signaling’.

Click on the top pathway hit. This will open it in the Pathway Browser.

Ignoring the diagram for now, look at the Pathways tab on the left.

How many sub-pathways does this pathway have?

How many reactions are in the first of these sub-pathways?

What reaction follows Notch 2 precursor transport to Golgi?

Hint: If it’s not visible, open the Details pane at the bottom of the page by clicking on the blue triangle.


The pathway browser pathway diagrams
The Pathway Browser - Pathway Diagrams

Boxes are proteins, sets or complexes.

Ovals are small molecules.

Green boxes are proteins or sets, blue are complexes.

Regulation

+ve -ve

Input

Reaction node

Catalyst

Outputs

Compartment

Transition Binding Dissociation Omitted Uncertain


Exercise 3
Exercise 3

From the Homepage, search for the pathway ‘Effects of PIP2 hydrolysis’ and open it in the Pathway Browser.

What symbol represents the reaction for ‘Binding of IP3 to the IP3 receptor’?

2. What symbol represents the reaction ‘Transport of Ca++ from platelet dense tubular system to cytoplasm’? What subtype of reaction is this?

3. What is the catalyst (descriptive name) for ‘2-AG hydrolysis to arachidonate by MAGL’? Can you find its UniProt ID and name the two outputs of this reaction?


Navigating in the pathway browser i
Navigating in the Pathway Browser I

Home and Analyze buttons

Search

Click here

Highlights

Details here

Click here to open pathway diagram...


Navigating in the pathway browser ii
Navigating in the Pathway Browser II

Highlights

Details here

Click here

Zoom






Pathway analysis overrepresentation
Pathway Analysis – Overrepresentation

‘Top-level’

Reveal next level

P-val


Exercise 6
Exercise 6

Check this!

What is the most significantly over-represented top-level pathway for this dataset?

How many genes are in this pathway, and how many were represented in the dataset?

Why is the top-level pathway Chromosome Maintenance higher in the list than Signalling by Wnt when the latter has a more significant probability score? (Hint – use the Open All button)

Can you interpret these results in terms of the underlying biology? (Hint: good luck, there are many correct answers!)



Species comparison ii
Species Comparison II

Yellow = human/rat

Blue = human only

Grey = not relevant

Black = Complex




Expression analysis ii

‘Hot’ = high

‘Cold’ = low

Expression Analysis II

Step through

Data columns




Exercise 9
Exercise 9

Open the pathway diagram for Netrin-1 Signaling.

Find the protein FADK1 (top centre of the cytosol). Right click on it and select Display Interactors. How many are there?

How many times has the interaction between FADK1 and Tumor endothelial marker 6 been documented? Hint: This detail is not in Reactome.

Find the protein SRC (to the left of FADK1). Display interactors for this protein. How many are there? Can you get a list of them?

Display interactors for UNC5B (bottom left of the cytosol). What happens and why?

What is the easiest way to remove interactors?




Biomart attributes
BioMart – attributes

Check to get

attribute





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