a database of human biological pathways janna hastings james watson
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A Database of human biological pathways Janna Hastings James Watson. Rationale – Journal information. Nature 407(6805):770-6.The Biochemistry of Apoptosis. - PowerPoint PPT PresentationTRANSCRIPT
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A Database of human biological pathways
Janna Hastings James Watson
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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 maybe reuse it?
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Nature. 2000 Oct 12;407(6805):770-6.The biochemistry of apoptosis.
Rationale - FiguresA picture paints a thousand words…
but….• Just pixels• Omits key details• Assumes• Fact or Hypothesis?
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Reactome is…
Free, online, open-source curateddatabase of pathways and reactions in human biology
Authored by expert biologists, maintained byReactome editorial staff (curators)
Mapped to cellular compartment
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Extensively cross-referenced
Tools for data analysis – Pathway Analysis, Expression Overlay, Species Comparison, Biomart…
Used to infer orthologous events in 20 non-human species
Reactome is…
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Theory - Reactions
Pathway steps = the “units” of Reactome
= events in biology
TRANSPORTCLASSIC
BIOCHEMICAL
BINDING
DISSOCIATION
DEGRADATION
PHOSPHORYLATION
DEPHOSPHORYLATION
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Reaction Example 1: Enzymatic
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Reaction Example 2: Transport
REACT_945.4
Transport of Ca++ from platelet dense tubular system to cytoplasm
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Other Reaction Types
Binding
Dimerization
Phosphorylation
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Reactions Connect into Pathways
OUTPUTINPUT
CATALYST
OUTPUTINPUT
CATALYST
INPUT OUTPUT
CATALYS
T
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Human pathway
PMID:5555 PMID:4444
mouse
cow
Direct evidence
Indirect evidencePMID:8976
PMID:1234
Evidence Tracking – Inferred Reactions
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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
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Species Selection
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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
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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
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Coverage – Current TOC
And many more...
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Planned Coverage – Editorial Calendar
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Reactome Tools
Interactive Pathway Browser
Pathway Mapping and Over-representation
Expression overlay onto pathways
Molecular Interaction overlay
Biomart
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Arabidopsis Reactome
http://www.arabidopsisreactome.org/
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Tutorial
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Front Page http://www.reactome.org
Main text
Navigation bar
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Exercise 1
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The Pathway BrowserSpecies selector
Search & Analyze barSidebar
Pathway Diagram Panel
Details Panel (hidden)Thumbnail
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Pathways tab – pathway hierarchy
PathwayReactionBlack-box
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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.
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The Pathway Browser - Pathway Diagrams
Boxes are proteins, sets or complexes. Ovals are small molecules.Green boxes are proteins or sets, blue are complexes.
Catalyst
Input
Outputs
Compartment
Reaction node
Transition Binding Dissociation Omitted Uncertain
Regulation+ve -ve
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Exercise 3
From the Homepage, search for the pathway ‘Effects of PIP2 hydrolysis’ and open it in the Pathway Browser.
1. What symbol represents the reaction for ‘Binding of IP3 to the IP3 receptor’?
2. 2. What symbol represents the reaction ‘Transport of Ca++ from platelet dense tubular system to cytoplasm’? What subtype of reaction is this?
3. 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?
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Navigating in the Pathway Browser I
Click here
Highlights
Details here
Click here to open pathway diagram...
Home and Analyze buttonsSearch
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Highlights
Details here
Navigating in the Pathway Browser II
Click here
Zoom
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Exercise 4
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The Details Panel
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Exercise 5
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Pathway Analysis
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Pathway Analysis – Overrepresentation
‘Top-level’
Reveal next level
P-val
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Exercise 6
Check this!
1. What is the most significantly over-represented top-level pathway for this dataset?
2. How many genes are in this pathway, and how many were represented in the dataset?
3. 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)
4. Can you interpret these results in terms of the underlying biology? (Hint: good luck, there are many correct answers!)
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Species Comparison I
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Species Comparison II
Yellow = human/rat Blue = human onlyGrey = not relevantBlack = Complex
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Exercise 7
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Expression Analysis I
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Expression Analysis II ‘Hot’ = high‘Cold’ = low
Step throughData columns
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Exercise 8
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Molecular Interaction Overlay
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Exercise 9
Open the pathway diagram for Netrin-1 Signaling.
1.Find the protein FADK1 (top centre of the cytosol). Right click on it and select Display Interactors. How many are there? 2.How many times has the interaction between FADK1 and Tumor endothelial marker 6 been documented? Hint: This detail is not in Reactome.3.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?4.Display interactors for UNC5B (bottom left of the cytosol). What happens and why?5.What is the easiest way to remove interactors?
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BioMart – selecting your dataset
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BioMart – filters
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BioMart – attributes
Check to get
attribute
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BioMart – results
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Exercise 10
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The End