May 2015 The Reactome Pathway Database Steve Jupe

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 reuse it?

Nature Oct 12;407(6805): The biochemistry of apoptosis. Rationale - Figures A picture paints a thousand words… but…. Just pixels Omits key details Assumes Fact or Hypothesis?

What is Reactome? Open source human pathway knowledgebase Metabolism, signaling, all other biological processes. Normal and disease-related pathways Mapped to cellular compartment Every event is supported by published experiment (citations are included). Authored by expert biologists, maintained by professional Curators Tools for data analysis and visualization Understanding gene lists or expression data - map to pathways. Downloads and API to support Computational Biology

Data – Primary External Sources GO Molecular Function Compartment Biological process UniProt – proteins ChEBI – small molecules Ensembl – genes and transcripts RNA Central - ncRNAs PubMed – literature evidence

Theory - Reactions Pathway steps = unit of Reactome = events in biology TRANSPORT CLASSIC BIOCHEMICAL BINDING DISSOCIATION DEGRADATION PHOSPHORYLATION DEPHOSPHORYLATION

Reactions Connect into Pathways OUTPUT INPUT CATALYST OUTPUT INPUT CATALYST INPUT OUTPUT CATALYST Pathway Reaction

Human pathway PMID:5555PMID:4444 mouse cow Direct evidence Indirect evidence PMID:8976 PMID:1234 Model Organisms – Inferred Reactions

Curation Version 52 has annotations for: 7951 human proteins, 795 mutant variants (137 disease- associated proteins), 1307 small molecules, 8169 reactions, 1762 pathways, literature references.

Data Curation Process Curator (10 Reactome staff) ExpertReviewer Pathways are authored and reviewed by an expert biologist Curator works with Author to represent the data in the Reactome data structure New data release every 3 months Regular Pathway updates. ORCID IDs used as attribution for Reactome - increases the visibility of expert contributions (authors, reviewers and curators).

Data Expansion – Human to Other Species A + ATP A + ADP -P B Human A + ATP A + ADP -P B Mouse B A Fly Reaction not inferred No orthologue - Protein not inferred + ATP

Downloads Pathways from Pathway Browser as text, PDF, etc. Entire database contents (and software) from Downloads page (see Homepage). Reusable standard formats BioPAX, SBML UniProt to Pathways GO annotations Protein-Protein interaction pairs - Interactions between proteins in the same complex, reaction, or adjoining reaction

The Pathway Browser - Pathway Diagrams Transition Binding Dissociation Omitted Uncertain Regulation +ve -ve Catalyst Inputs Outputs Compartment Reaction node

Disease annotation in Reactome Three main areas: Infection (eg. HIV, influenza, botulism) microbially-expressed proteins Cancer (eg. EGFR, FGFR and NOTCH signalling) altered protein functions Metabolic diseases (eg. mucopolysaccharidoses, phenylketonuria, vitamin metabolism abnormalities) altered expression of proteins

Disease display in Reactome Loss of function in metabolism HIV infection Altered protein function in Cancer

Reactome Website and Tools

Full Text Search

Search Details

The Pathway Browser Home buttonSpeciesShow/hide Panels Diagram key Analyze Data Hierarchy Panel Thumbnail Zoom/Move Pathway Panel Detail Panel Search and Configure Quick Tour

Pathway Overview 22

Protein Structures from PDBe

Expression Data from GXA

Illustrations 25

The Big List of Differentially Pathways and Experiment Expressed Molecules beyond….. Understanding gene lists…Reactome Tools

Analysis – identifier list

Over-representation FDR

Pathway topology matching

Expression overlay I

Expression overlay II Yellow = high Blue = low Step through Data columns

Species Comparison I

Species Comparison II Yellow = human/rat Blue = human only No colour = no data

Molecular Interaction Overlay

More Information From the Reactome Homepage Reactome User Guide Train Online -

Conclusions Reactome is a curated database of human biological pathways. Web site provides tools for visualizing and interpreting your experimental data. Downloadable as a data framework for systems biology modeling. All Reactome data and software are open, no licensing is required.

Phani Garapati Marc Gillespie Robin Haw Bijay Jassal Steve Jupe Maximilian Koch Bruce May Sheldon MacKay Lisa Matthews Antonio Fabregat Marija Orlic-Milacic Karen Rothfels Veronica Shamovsky Konstantinos Sidiropoulos Marissa Webber Joel Weiser Guanming Wu Henning Hermjakob Peter D’Eustachio Lincoln Stein Acknowledgements

Thank you Questions, comments and suggestions