Dec 16, 2015
www.reactome.org May 20122
Rationale – Journal informationNature 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 reuse it?
www.reactome.org May 20123
Nature. 2000 Oct 12;407(6805):770-6.The biochemistry of apoptosis.
Rationale - Figures A picture paints a thousand words…
but….• Just pixels• Omits key details• Assumes• Fact or Hypothesis?
www.reactome.org May 20124
Reactome is…
Free, online, open-source curateddatabase of pathways and reactions in human biology
Authored by expert biologists, maintained by Reactome editorial staff (curators)
Mapped to cellular compartment
www.reactome.org May 20125
Extensively cross-referenced
Tools for data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart…
Used to infer orthologous events in 20 other species
Reactome is…
www.reactome.org May 20126
human
PMID:5555 PMID:4444
mouse
cow
Direct evidence
Direct evidence
Indirect evidence
PMID:8976
PMID:1234
Using model organism data to build pathways – Inferred pathway events
www.reactome.org May 20127
Theory - Reactions
Pathway steps = the “units” of Reactome
= events in biology
TRANSPORTCLASSIC
BIOCHEMICAL
BINDING
DISSOCIATION
DEGRADATION
PHOSPHORYLATION
DEPHOSPHORYLATION
www.reactome.org May 20129
Reaction Example 2: Transport
REACT_945.4
Transport of Ca++ from platelet dense tubular system to cytoplasm
www.reactome.org May 201211
Reactions Connect into Pathways
OUTPUTINPUT
CATALYST
OUTPUTINPUT
CATALYST
INPUT OUTPUT
CATALYST
www.reactome.org May 201212
Human pathway
PMID:5555 PMID:4444
mouse
cow
Direct evidence
Indirect evidencePMID:8976
PMID:1234
Evidence Tracking – Inferred Reactions
www.reactome.org May 201213
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
www.reactome.org May 201215
Data Expansion – Projecting to Other Species
A + ATP A + ADP-PB
Human
A + ATP A + ADP-P
BMouse
BA
Drosophila
Reaction notinferred
No orthologue - Protein not inferred
+ ATP
www.reactome.org May 201216
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
www.reactome.org May 201219
Reactome Tools
• Interactive Pathway Browser
• Pathway Mapping and Over-representation
• Expression overlay onto pathways
• Molecular Interaction overlay
• Biomart
www.reactome.org May 201223
The Pathway BrowserSpecies selector
Diagram Key
Sidebar
Pathway Diagram Panel
Details Panel (hidden)
Zoom/move toolbar
Thumbnail
www.reactome.org May 201225
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.
1. How many sub-pathways does this pathway have?2. How many reactions are in the first of these sub-pathways?3. 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.
www.reactome.org May 201226
The Pathway Browser - Pathway Diagrams
Boxes are proteins, protein sets, mixed sets or complexes. Ovals are small molecules (or sets of) Green boxes are proteins or sets, blue are complexes.
Catalyst
Input
Outputs
Compartment
Reaction node
Transition Binding Dissociation Omitted Uncertain
Regulation+ve -ve
www.reactome.org May 201228
Navigating in the Pathway Browser I
Click here
Highlights
Details here
Click here to open pathway diagram...
Home and Analyze buttons
www.reactome.org May 201229
Details here
Navigating in the Pathway Browser II
Click here
ZoomHighlights
www.reactome.org May 201234
Pathway Analysis – Overrepresentation
‘Top-level’
Reveal next level
P-val
www.reactome.org May 201237
Species Comparison II
Yellow = human/rat Blue = human onlyGrey = not relevantBlack = Complex
www.reactome.org May 201240
Expression Analysis II ‘Hot’ = high‘Cold’ = low
Step throughData columns