SPIKE: a database of highly curated human signaling pathways

Abstract

The rapid accumulation of knowledge on biological signaling pathways and their regulatory mechanisms has highlighted the need for specific repositories that can store, organize and allow retrieval of pathway information in a way that will be useful for the research community. SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. To make database population and pathway comprehension straightforward, a simple yet informative data model is used, and pathways are laid out as maps that reflect the curator’s understanding and make the utilization of the pathways easy. The database currently focuses primarily on pathways describing DNA damage response, cell cycle, programmed cell death and hearing related pathways. Pathways are regularly updated, and additional pathways are gradually added. The complete database and the individual maps are freely exportable in several formats. The database is accompanied by a stand-alone software tool for analysis and dynamic visualization of pathways.

Figure 1.

SPIKE’s data model and links with other databases. (A) The data model. SPIKE’s data model includes five types of biological entities (nodes in SPIKE maps) and three types of relationships between entities (edges in the maps). The types of entities are: (i) Genes/Proteins. Protein-coding genes are displayed in the maps as violet (e.g. ATM in the figure); non-coding genes are light-blue nodes (e.g. MIR34C). (ii) Families (yellow nodes, e.g. MIR-34), (iii) Complexes (green nodes, MRN), (iv) Chemical molecules (orange nodes, wortmannin) and (v) General entities (dark-pink nodes; e.g. ‘cell-cycle progression’ in this map). The types of relationships are: (i) Containment links between families or complexes and their members, shown as green edges (e.g. miR34B is contained in the MIR-34 family). (ii) Regulations, displayed as directed blue edges; arrows represent positive regulation (e.g. ATM activates TP53) and T-shape edges indicate negative regulation (e.g. wortmannin inhibits ATM). (iii) Interactions shown as undirected blue edges (not included in this figure). Red/green dots within a node indicate that the node has additional regulations/containments in the SPIKE database that are not included in the map. The dots on the edges can be used in the SPIKE stand-alone version to identify the literature reference to the relationship and as a handle to move the edge center in the map for better visualization. (B) SPIKE data sources and interlinks with external databases. The upper tier of SPIKE database contains highly curated data either uploaded by SPIKE curators or contributed by experts in various domains in the biomedical research. Each regulation uploaded by the curators or experts is supported and linked to at least one reference (PubMed). In addition, SPIKE imports data from external signaling databases and protein–protein databases and large-scale data sets. Data uploaded to SPIKE database receive quality flag that indicate their reliability level (see text for details); in this figure data sources are color-coded according to the quality flag they are assigned to: Data uploaded by SPIKE curators and domain experts get the highest quality level; Data imported from external curated signaling databases are assigned intermediate quality level (since these data are imported automatically and en masse into SPIKE database) and data imported from protein–protein interaction databases and data sets get low quality level. SPIKE genes and chemical molecules are imported from Entrez-Genes and ChEBI, respectively.

Figure 2.

Browsing SPIKE database. Basic searching utilities over SPIKE database are provided in the website. In this example the BRCA1 gene was searched. Pertinent information about the gene and a list of the maps in which it is included are displayed to the user.

Figure 3.

Autophagy map. Autophagy, or ‘self eating’, is the process by which de novo-formed double-membrane enclosed vesicles, known as autophagosomes, engulf cytosolic components and organelles, and ultimately fuse with the lysosome, enabling degradation of its internal contents. Autophagy serves as a means of recycling critical cellular building blocks, especially in times of deprivation and stress, and removal of damaged organelles, and misfolded and aggregated proteins. The main regulators and effectors of this process and interlinks between them are depicted in the map. The induction of autophagy is modulated by several signaling pathways which converge at the activation of the mTOR/ULK complex (right part of the map) and of Class III PI3K complex (center). Two ubiquitin-like pathways (left part of the map) mediate the elongation of autophagosome membranes.