Here, signal transduction through the canonical NF-κB and the Wnt/β-catenin signalling pathway is investigated under wild-type and cancerous conditions. Signal transduction in both pathways depends on ubiquitination and proteasomal degradation of central pathway components mediated by β-transducin repeat-containing proteins (β-TrCP). Hence, conditions are explored that enable or prevent potential crosstalk by competitive β-TrCP sequestration. The analyses offer mechanistic explanations to account for conflicting experimental observations concerning the mutual impact of NF-κB and Wnt/β-catenin signalling. Since expression of the two mammalian β-TrCP paralogues FWD1/β-TrCP1 and HOS/β-TrCP2 is regulated by Wnt/β-catenin signalling, two transcriptional feedback mechanisms are established in the signalling network adding to its complexity. The specific impact of each feedback is thoroughly dissected casting doubts on the current notion of functional redundancy of FWD1 and HOS.