Investigation of noncanonical Wnt signaling network in C. elegans

Abstract

Wnt proteins, a well conserved family of signalling molecules, initiate signalling mechanisms that play important roles in embryonic development of animals. Wnt proteins activate three distinct signalling pathways. Wnt/β-catenin pathway is the canonical signalling pathway whereas Wnt/PCP and Wnt/Ca2+ are the β-catenin independent noncanonical pathways. Wnt-activated excessive β-catenin accumulation in nucleus is reported to cause tumour formation in different cells. On the other hand, one of the β-catenin independent signalling pathways; the Wnt/Ca2+ signalling pathway, is found to antagonize Wnt/β-catenin signalling pathway. Therefore, Wnt/Ca2+ cascade may have the ability to act as a tumour suppressor. Caenorhabditis elegans as an extremely suitable model to evaluate the functions of disease genes incorporates a well conserved set of Wnt signalling proteins. In the present computational study, Wnt signalling mechanisms that are involved in the developmental processes and tumorigenesis are investigated thoroughly in C. elegans. In order to better understand the molecular basis underlying the ability of Wnt proteins performing antagonistic or similar signalling activities, the protein-protein and domain-domain interaction networks of Wnt/Ca2+ signalling proteins were reconstructed using literature information and homology based modelling. The reconstructed network is further investigated at micro scale whether the majority of the genes in Wnt/Ca2+ signalling pathway are conserved during evolution and at macro scale whether the proposed Wnt/Ca2+ signalling network is biologically significant. The reconstructed network having a scale-free topology like most of the other biological networks successfully covers most of the protein and domain interactions of the Wnt/Ca2+ signalling mechanism in humans and hence can be used in studies for identifying drug targets.