β-catenin–β-TrCP interaction

The β-catenin–β-TrCP interaction is a critical post-translational protein–protein interaction at the heart of canonical Wnt signaling and proteasome-mediated degradation of β-catenin. β-catenin (encoded by CTNNB1) is a transcriptional co-activator that accumulates in the nucleus in response to Wnt pathway activation, enabling transcription of Wnt target genes. In the absence of Wnt signaling, β-catenin is phosphorylated by the destruction complex (notably by GSK-3β) and then recognized by the F-box protein β-TrCP (encoded by BTRC), a substrate recognition component of the SCF (Skp1–Cullin–F-box) E3 ubiquitin ligase complex. Only phosphorylated β-catenin is bound by β-TrCP, triggering its polyubiquitination and proteasomal degradation. Disruption of this interaction, either by genetic mutation (e.g., in β-catenin phosphorylation sites) or by pathway deregulation (e.g., in cancers), results in accumulation of β-catenin and aberrant activation of Wnt transcriptional programs, contributing to tumorigenesis. Pharmacological agents that modulate this interaction, either enhancing it (to promote degradation in cancer) or inhibiting it (to stabilize β-catenin for potential regenerative therapies), are under development as targeted therapies[1][3][7][8][9]

Other names

Beta-catenin–beta-Transducin repeat-containing protein interactionCTNNB1–BTRC interactionβ-catenin–SCFβTrCP interactionβ-catenin:β-TrCP complex

Small molecules can enhance the β-catenin/β-TrCP interaction, promoting β-catenin degradation (potential anti-cancer mode of action) Inhibitors of β-TrCP block interaction, preventing β-catenin (and other substrate) degradation, with possible application in pathologies involving excessive protein turnover[9] Molecular glues that stabilize or promote the recruitment of β-catenin to β-TrCP, triggering ubiquitination[3]