Topological alternate centrality measure capturing drug targets in the network of MAPK pathways

Abstract

A new centrality of the nodes in the network is proposed called alternate centrality, which can isolate effective drug targets in the complex signalling network. Alternate centrality metric defined over the network substructure (four nodes - motifs). The nodes involving in alternative activation in the motifs gain in metric values. Targeting high alternative centrality nodes hypothesised to be destructive free to the network due to their alternative activation mechanism. Overlapping and crosstalk among the gene products in the conserved network of MAPK pathways selected for the study. In silico knock-out of high alternate centrality nodes causing rewiring in the network is investigated using MCF-7 breast cancer cell line-based data. Degree of top alternate centrality nodes lies between the degree of bridging and pagerank nodes. Node deletion of high alternate centrality on the centralities such as eccentricity, closeness, betweenness, stress, centroid and radiality causes low perturbation. The authors identified the following alternate centrality nodes ERK1, ERK2, MEKK2, MKK5, MKK4, MLK3, MLK2, MLK1, MEKK4, MEKK1, TAK1, P38alpha, ZAK, DLK, LZK, MLTKa/b and P38beta as efficient drug targets for breast cancer. Alternate centrality identifies effective drug targets and is free from intertwined biological processes and lethality.

Fig. 1

In Motif M1, nodes getting inwards edges are Node 1, Node 4. Each alternatively activating substrate nodes is getting value Node 1, Node 2 and Node 3. Inhibition of one of the nodes (Node 1, Node 2 and Node 3) can be taken care by an alternative node(s)

Fig. 2

PMQGF 4 node motif highlighted in MAVisto

Fig. 3

Directed network of MAPK pathways

Fig. 4

Number of side effects comparison among top bridging, alternate and pagerank centrality nodes

Fig. 5

Knock‐out analysis of 17 top alternate centrality nodes