Highly interconnected networks of signaling proteins mediate complex biological processes such as development, tissue function, and proliferation. Since aberrations in these signaling networks underlie a variety of pathologies, understanding the quantitative and dynamic behavior of these networks will be essential for engineering effective disease therapeutics. Two signaling pathways that are prominent in oncogenesis are the Wnt signaling pathway and the epidermal growth factor (EGF) signaling pathway. The key effector of the canonical Wnt signaling pathway is the intracellular protein β-catenin, which activates transcription of cell cycle genes upon stimulation with Wnt ligands. Recently, we demonstrated that EGF, a non-Wnt ligand, can activate transcription of cell-cycle genes by β-catenin; here, we extend those results and demonstrate that the canonical Wnt ligand Wnt 3a activates transcription of β-catenin target genes with dynamics quantitatively similar to those of EGF-mediated β-catenin signaling. Using biochemical assays and a suite of pharmacological inhibitors, we have uncovered that EGF and Wnt 3a utilize both common and distinct molecular mechanisms to induce the transcription of β-catenin target genes, suggesting a novel crosstalk between canonical Wnt and EGF signaling. The tightly coupled, quantitative synergy between these two prominent oncogenic pathways may provide insight into the sophisticated biomolecular networks underlying oncogenesis, as well as suggest new molecular targets for the treatment of cancer.

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