Protein kinase CK2 in breast cancer: the CK2β regulatory subunit takes center stage in epithelial plasticity

Abstract

Structurally, protein kinase CK2 consists of two catalytic subunits (α and α') and two regulatory subunits (β), which play a critical role in targeting specific CK2 substrates. Compelling evidence shows the complexity of the CK2 cellular signaling network and supports the view that this enzyme is a key component of regulatory protein kinase networks that are involved in several aspects of cancer. CK2 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, and its expression and activity are upregulated in blood tumors and virtually all solid tumors. The prognostic significance of CK2α expression in association with various clinicopathological parameters highlighted this kinase as an adverse prognostic marker in breast cancer. In addition, several recent studies reported its implication in the regulation of the epithelial-to-mesenchymal transition (EMT), an early step in cancer invasion and metastasis. In this review, we briefly overview the contribution of CK2 to several aspects of cancer and discuss how in mammary epithelial cells, the expression of its CK2β regulatory subunit plays a critical role in maintaining an epithelial phenotype through CK2-mediated control of key EMT-related transcription factors. Importantly, decreased CK2β expression in breast tumors is correlated with inefficient phosphorylation and nuclear translocation of Snail1 and Foxc2, ultimately leading to EMT induction. This review highlights the pivotal role played by CK2β in the mammary epithelial phenotype and discusses how a modest alteration in its expression may be sufficient to induce dramatic effects facilitating the early steps in tumor cell dissemination through the coordinated regulation of two key transcription factors.

Effects of CK2β subunit down-regulation on Akt signalling in HK-2 renal cells

“…GSK3β S9 phosphorylation and deactivation is known to regulate the expression of Snail1 protein induced by TGF-β1 in HK-2 cells [49]. Moreover, GSK3β phosphorylation and destabilization of Snail1 requires the priming phosphorylation of Snail1 by CK2, a process reported to be dependent on CK2β [32,61]. However, we have now observed that the LY294002 induced decrease in GSK3β S9 phosphorylation was accompanied by a decrease in Snail1 levels both in control and in CK2β downregulated HK-2 cells.…”

“…On the other hand, CK2β might influence substrate specificity, since there are protein substrates whose phosphorylation is specifically catalysed by either the free catalytic subunits or CK2 holoenzyme [3]. Moreover, CK2β also binds to a wide range of other cellular proteins and acts as a regulatory binding partner of certain protein kinases [9][10][11], suggesting that it can exert cellular functions other than its incorporation into CK2 holoenzyme.…”

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

“…CSNK2 is generally considered to be a constitutively active enzyme (i.e., its catalytic subunits do not require activating phosphorylation, association with its regulatory subunit, or the presence of second messengers to be catalytically active), which is expressed at higher levels in many forms of human cancer (1,3,7,8). CSNK2 has also been shown to be essential for viability and to enhance cancer cell survival associated with inhibition of apoptosis.…”

Quantitative Analysis of Dynamic Protein Interactions during Transcription Reveals a Role for Casein Kinase II in Polymerase-associated Factor (PAF) Complex Phosphorylation and Regulation of Histone H2B Monoubiquitylation

“…CKII contributes to the pathology of many human cancers (21)(22)(23). Multiple complexes containing CKII have been identified, including the transcription elongation factor FACT (16,24).…”