NCMine: Core-peripheral based functional module detection using near-clique mining

Abstract

Motivation: The identification of functional modules from protein-protein interaction (PPI) networks is an important step toward understanding the biological features of PPI networks. The detection of functional modules in PPI networks is often performed by identifying internally densely connected subnetworks, and often produces modules with "core" and "peripheral" proteins. The core proteins are the ones having dense connections to each other in a module. The difference between core and peripheral proteins is important to understand the functional roles of proteins in modules, but there are few methods to explicitly elucidate the internal structure of functional modules at gene level.

Results: We propose NCMine, which is a novel network clustering method and visualization tool for the core-peripheral structure of functional modules. It extracts near-complete subgraphs from networks based on a node-weighting scheme using degree centrality, and reports subgroups as functional modules. We implemented this method as a plugin of Cytoscape, which is widely used to visualize and analyze biological networks. The plugin allows users to extract functional modules from PPI networks and interactively filter modules of interest. We applied the method to human PPI networks, and found several examples with the core-peripheral structure of modules that may be related to cancer development.

Availability and implementation: The Cytoscape plugin and tutorial are available at Cytoscape AppStore. (http://apps.cytoscape.org/apps/ncmine).

Contact: kengo@ecei.tohoku.ac.jpSupplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1.

Recall and precision calculated from cluster extraction results by comparing extracted clusters and actual embedded clusters in artificial networks. Higher recall and precision indicate better performance

Fig. 2.

(A) Comparison of cliqueness of clusters extracted by each method. (B) Comparison of the sizes of extracted clusters and known protein complexes (C) Relationship between node degree and cluster membership calculated from the NCMine cluster extraction results. Genes included in the plot are listed in Supplementary Table S1(A) and (B)

Fig. 3.

(A) Two sets of peripheral proteins (blue and red) with the same core proteins (green) are shown. In this example, most of the proteins were related to cancer development. However, the proteins that participate in blue peripherals and red peripherals had different functions. Genes in the clusters: AKT1: v-akt murine thymoma viral oncogene homolog 1; AR: Androgen receptor; BRCA1: Breast cancer 1, early onset; CREBBP: CREB-binding protein; CTNNB1: Catenin (cadherin-associated protein), beta 1, 88 kDa; EP300: E1A-binding protein p300; ESR1: Estrogen receptor 1; JUN: Jun proto-oncogene; RB1: Retinoblastoma 1; RELA: v-rel avian reticuloendotheliosis viral oncogene homolog A; SMAD1: SMAD family member 1; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SMAD4: SMAD family member 4; SP1: Sp1 transcription factor; STAT3: Signal transducer and activator of transcription 3 (acute-phase response factor); TP53: Tumor protein p53; UBE2I: Ubiquitin-conjugating enzyme E2I (B) Most of the core-proteins (green) were involved in the Wnt signaling pathway, which is related to cancer, generally; however, peripheral-proteins involved specific cancer development pathways. Genes in the clusters: AKT1: v-akt murine thymoma viral oncogene homolog 1; AR: Androgen receptor; BRCA1: Breast cancer 1, early onset; CREBBP: CREB-binding protein; CTNNB1: Catenin (cadherin-associated protein), beta 1, 88 kDa; EP300: E1A-binding protein p300; ESR1: Estrogen receptor 1; JUN: Jun proto-oncogene; MAPK1: Mitogen-activated protein kinase 1; RB1: Retinoblastoma 1; SMAD1: SMAD family member 1; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SMAD4: SMAD family member 4; SMAD9: SMAD family member 9; SP1: Sp1 transcription factor; STAT3: Signal transducer and activator of transcription 3 (acute-phase response factor); TGFBR1: Transforming growth factor, beta receptor 1; TP53: Tumor protein p53; UBE2I: Ubiquitin-conjugating enzyme E2I

Fig. 4.

Cytoscape plugin for NCMine, and basic workflow