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

Abstract

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 β-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 β-catenin. Interestingly, although there is no interaction between RACK1 and β-catenin, RACK1 binds PSMD2 competitively with β-catenin. Moreover, RACK1 prevents ubiquitinated β-catenin from binding to PSMD2, thereby protecting β-catenin from proteasomal degradation. Collectively, our findings uncover a novel mechanism by which RACK1 increases β-catenin stability and promotes breast cancer proliferation.

RACK1 Promotes Meningioma Progression by Activation of NF-κB Pathway via Preventing CSNK2B from Ubiquitination Degradation

“…It has been shown that RACK1 is closely related to tumor progression [19,[21][22][23][24][25] due to its modulation of multiple signaling pathways including PKC, receptor tyrosine kinase/PI3K/AKT, ERK/MAPK, STAT3, Src/FAK, NF-κB, Wnt/β-catenin, and RhoA/Rho pathway [26,[34][35][36][37]. RACK1 affects various behaviors such as cell cycle, cell proliferation, migration and invasion, epithelial mesenchymal transition, and tumor cell differentiation via these signal pathways.…”

“…RACK1 could enhance the ability of self-renewal and chemoresistance of cancer stem cells in human hepatocellular carcinoma [19] and was reported to facilitate the development and lymph node metastasis of cervical cancer [21]. Besides, RACK1 may promote the ability of proliferation and the tendency of invasion and metastasis of breast cancer [22], and the decrease of ubiquitin degradation of RACK1 in ovarian cancer leads to the enhancement of the proliferation, migration, and invasion of ovarian cancer cells [23]. In the central nervous system, some studies have shown that RACK1 promotes the proliferation and invasion of glioma cells and may also affect the differentiation and apoptosis of glioma cells [24,25], but so far there are no studies on RACK1 in meningiomas.…”

Stress granules in cancer: Adaptive dynamics and therapeutic implications

“… 132 RACK1 is implicated in the progression and development of drug resistance in a variety of cancers, including oral, gastric, breast, colon, cervical, liver, and osteosarcoma. 133 , 134 , 135 Specifically, RACK1 modulates signaling pathways like MEK/ERK, NF-κB, induces autophagy, mediates Src-dependent tyrosine phosphorylation of Anxa2, and activates the AKT/mTOR/ASCT2 axis, which drive cancer progression. 136 , 137 , 138 Furthermore, it was shown that in colon cancer, Rbfox2 (Fox-1 homolog 2), induced by resveratrol treatment, dissociates from SGs to prevent cancer tissue progression.…”