FMRP recruitment of β-catenin to the translation pre-initiation complex represses translation.

Canonical Wnt/β-catenin signaling is an essential regulator of various cellular functions throughout development and adulthood. Aberrant Wnt/β-catenin signaling also contributes to various pathologies including cancer, necessitating an understanding of cell context-dependent mechanisms regulating this pathway. Since protein-protein interactions underpin β-catenin function and localization, we sought to identify novel β-catenin interacting partners by affinity purification coupled with tandem mass spectrometry in vascular smooth muscle cells (VSMCs), where β-catenin is involved in both physiological and pathological control of cell proliferation. Here, we report novel components of the VSMC β-catenin interactome. Bioinformatic analysis of the protein networks implies potentially novel functions for β-catenin, particularly in mRNA translation, and we confirm a direct interaction between β-catenin and the fragile X mental retardation protein (FMRP). Biochemical studies reveal a basal recruitment of β-catenin to the messenger ribonucleoprotein and translational pre-initiation complex, fulfilling a translational repressor function. Wnt stimulation antagonizes this function, in part, by sequestering β-catenin away from the pre-initiation complex. In conclusion, we present evidence that β-catenin fulfills a previously unrecognized function in translational repression.