The Reactome Pathway Knowledgebase 2024

Abstract

The Reactome Knowledgebase (https://reactome.org), an Elixir and GCBR core biological data resource, provides manually curated molecular details of a broad range of normal and disease-related biological processes. Processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Here we review progress towards annotation of the entire human proteome, targeted annotation of disease-causing genetic variants of proteins and of small-molecule drugs in a pathway context, and towards supporting explicit annotation of cell- and tissue-specific pathways. Finally, we briefly discuss issues involved in making Reactome more fully interoperable with other related resources such as the Gene Ontology and maintaining the resulting community resource network.

Graphical Abstract

Figure 1.

Disease variant-associated disease reactions in Reactome pathway diagrams. The pathway, ‘Intracellular signaling by second messengers (R-HSA-9006925)’ (A) includes a subpathway, ‘AKT phosphorylates targets in the nucleus (R-HSA-198693)’ (B) that shows normally regulated signaling mediated by AKT. The disease counterpart of the signaling pathway, ‘PI3K/AKT Signaling in Cancer (R-HSA-2219528) (C) includes a subpathway, ‘Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)’ (D) that shows constitutive AKT signaling due to a missense mutation that enables AKT to bypass normal negative regulation and become constitutively active.

Figure 2.

Annotation of cell- and tissue-specific reactions. A cell lineage path, ‘Development of keratinocytes in interfollicular skin epidermis’ (R-HSA-9725554) is represented as four cell development steps, equivalent to reactions. Each step transforms an input cell, equivalent to a physical entity, to an output cell, regulated by physical entities such as epidermal growth factor (EGF) and calcium ions (Ca²⁺). (A) A cell icon, ‘transit-amplifying cell of epidermis basal layer’ (R-HSA-9725625), highlighted with a red box in the pathway diagram panel (above) is annotated with cell and tissue ontology terms to identify and distinguish it from other kinds of cells and with protein and RNA markers that are key to its function in the process annotated here, listed in the details panel below the diagram. (B) A cell development step, ‘Transit-amplifying cell of basal layer produces keratinocyte of spinosum layer in skin epidermis’ (R-HSA-9727354) highlighted with a red box in the pathway diagram panel (above) is annotated with regulators of the transformation and identities of preceding and following development steps in the details panel below the diagram.