Cytoscape stringApp 2.0: Analysis and Visualization of Heterogeneous Biological Networks

Abstract

Biological networks are often used to represent complex biological systems, which can contain several types of entities. Analysis and visualization of such networks is supported by the Cytoscape software tool and its many apps. While earlier versions of stringApp focused on providing intraspecies protein-protein interactions from the STRING database, the new stringApp 2.0 greatly improves the support for heterogeneous networks. Here, we highlight new functionality that makes it possible to create networks that contain proteins and interactions from STRING as well as other biological entities and associations from other sources. We exemplify this by complementing a published SARS-CoV-2 interactome with interactions from STRING. We have also extended stringApp with new data and query functionality for protein-protein interactions between eukaryotic parasites and their hosts. We show how this can be used to retrieve and visualize a cross-species network for a malaria parasite, its host, and its vector. Finally, the latest stringApp version has an improved user interface, allows retrieval of both functional associations and physical interactions, and supports group-wise enrichment analysis of different parts of a network to aid biological interpretation. stringApp is freely available at https://apps.cytoscape.org/apps/stringapp.

Keywords: Cytoscape; STRING; cross-species interactions; enrichment analysis; heterogeneous networks; host−parasite; omics data; stringApp; virus−host.

Figure 1

Three example workflows for using stringApp in Cytoscape. While the first one is based on the analysis of proteomics data described in the previous stringApp publication, the second and third represent the two use cases described here, one focusing on an experimentally determined virus–host network and the other on a host–parasite network retrieved with stringApp. Colored boxes represent functionality implemented by stringApp.

Figure 2

stringApp Results panel in Cytoscape. The Nodes tab (left) provides quick access to changing different visual properties, running network analysis tasks, and filtering based on tissue and subcellular localization. It also contains a panel with information for each currently selected node, as shown for MCM3 (bottom right). The Edges tab allows users to change the network type and confidence as well as to filter and color the edges based on evidence.

Figure 3

Visualization of a STRINGified virus–host network. The network contains 332 high-confidence protein–protein interactions (red edges) between SARS-CoV-2 (dark red nodes) and human proteins (gray nodes) identified by affinity-purification mass spectrometry. stringApp was used to fetch high-confidence physical interactions between the human proteins (score cutoff ≥0.8, gray edges) and to retrieve enriched publications. One of the publications and the proteins it mentions are highlighted in the STRING Publications table (light blue line) and in the network view (yellow colored nodes).

Figure 4

Analysis of a malaria cross-species network with stringApp in Cytoscape. (A) stringApp user interface for cross-species queries. (B) stringApp Expand network options dialogue. (C) Network of H. sapiens (teal), P. falciparum (red), and A. gambiae (lime) proteins and their high-confidence inter- and intraspecies interactions (score cutoff 0.8). (D) All cross-species clusters after applying Markov clustering (MCL) on the network. Human proteins are colored based on the TISSUES confidence scores for liver.