RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin

The receptor for activated C kinase 1 (RACK1) is a key scaffolding protein with multifunctional and multifaceted properties. By mediating protein-protein interactions, RACK1 integrates multiple intracellular signals involved in the regulation of various physiological and pathological processes. Dysregulation of RACK1 has been implicated in the initiation and progression of many tumors. However, the exact function of RACK1 in cancer cellular processes, especially in proliferation, remains controversial. Here, we show that RACK1 is required for breast cancer cell proliferation in vitro and tumor growth in vivo. This effect of RACK1 is associated with its ability to enhance beta-catenin stability and activate the canonical WNT signaling pathway in breast cancer cells. We identified PSMD2, a key component of the proteasome, as a novel binding partner for RACK1 and beta-catenin. Interestingly, although there is no interaction between RACK1 and beta-catenin, RACK1 binds PSMD2 competitively with beta-catenin. Moreover, RACK1 prevents ubiquitinated beta-catenin from binding to PSMD2, thereby protecting beta-catenin from proteasomal degradation. Collectively, our findings uncover a novel mechanism by which RACK1 increases beta-catenin stability and promotes breast cancer proliferation.