Investigation of crosstalk between Wnt and Hedgehog signaling pathways

Abstract

In the last few years, an intense interest is being shown in the evolutionarily conserved signaling pathways which have crucial roles during embryonic development. The most intriguing factor behind this interest is that malfunctioning of these signaling pathways (Hedgehog, Notch, Wnt etc.) leads to several human diseases, especially to cancer. Furthermore, these signaling pathways are not isolated highways, contrarily they interact with each other in a number of ways. This study deals with the β-catenin dependent branch of Wnt signaling and the Hedgehog signaling pathways which offer potential targeting points for cancer drug development. Here, through integration of protein-protein interaction data and Gene Ontology annotations, the Wnt/β-catenin and Hedgehog signaling networks consisting of proteins with statistically high probability of being biologically related to these signaling pathways were reconstructed in D. melanogaster. The reconstructed networks have scale-free topologies like most of the other biological networks. Furthermore, the linear paths which mediate the signal from the input proteins to the output proteins were identified in these reconstructed networks using interacting proteins. The receptors (fz2 for the Wnt ligand and ptc for the Hedgehog ligand) were found to be involved in the linear paths with the highest participations following the input and output proteins for both Wnt and Hedgehog signaling networks. Lastly, the identification of 477 common proteins between the reconstructed Wnt/β-catenin (656 proteins) and Hedgehog signaling (568 proteins) networks revealed that these two signaling networks interact with each other. The identification of regulatory proteins functioning in these signaling networks is crucial toward efforts for preventing tumour formation. The proteins arm, frizzled receptors (fz and fz2), arr, Apc, Axn, ci and ptc, which have been reported as potential drug targets in the literature, were also detected as essential proteins in these networks.