Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction

Abstract

Epithelial-to-mesenchymal transition (EMT) is closely linked to conversion of early-stage tumours into invasive malignancies. Many signalling pathways are involved in EMT, but the key regulatory kinases in this important process have not been clearly identified. Protein kinase CK2 is a multi-subunit protein kinase, which, when overexpressed, has been linked to disease progression and poor prognosis in various cancers. Specifically, overexpression of CK2α in human breast cancers is correlated with metastatic risk. In this article, we show that an imbalance of CK2 subunits reflected by a decrease in the CK2β regulatory subunit in a subset of breast tumour samples is correlated with induction of EMT-related markers. CK2β-depleted epithelial cells displayed EMT-like morphological changes, enhanced migration, and anchorage-independent growth, all of which require Snail1 induction. In epithelial cells, Snail1 stability is negatively regulated by CK2 and GSK3β through synergistic hierarchal phosphorylation. This process depends strongly on CK2β, thus confirming that CK2 functions upstream of Snail1. In primary breast tumours, CK2β underexpression also correlates strongly with expression of EMT markers, emphasizing the link between asymmetric expression of CK2 subunits and EMT in vivo. Our results therefore highlight the importance of CK2β in controlling epithelial cell plasticity. They show that CK2 holoenzyme activity is essential to suppress EMT, and that it contributes to maintaining a normal epithelial morphology. This study also suggests that unbalanced expression of CK2 subunits may drive EMT, thereby contributing to tumour progression.

Equine Epidermis: A Source of Epithelial-Like Stem/Progenitor Cells with In Vitro and In Vivo Regenerative Capacities

“…Color images available online at www.liebertpub.com/scd expression in corneal stem cells [41,42] and circulating keratinocyte progenitor cells [32]. Moreover, the EpSCs in the present study were positive for Casein Kinase 2b, which is reputed to inhibit the development of the mesenchymal morphology and phenotype [37,45], and plays an important role in the functional regulation of epithelial cells [46][47][48].…”

“…S5B, C), but were clearly positive for the proliferation marker Ki67 [36] (Supplementary Fig. S6) and the epithelial marker Casein Kinase 2b [37] (Supplementary Fig. S6), both of which sharply decreased on differentiation (Supplementary Fig.…”

“…Casein Kinase 2b and Ki67 indicated where proliferating [36] epithelial [37] cells were located within the sample. To examine the role of EpSCs in elastin production and neovascularization, tissue sections were stained with mouse anti-bovine elastin IgG 1 (Leica; clone BA-4, 1:100) and rabbit anti-human vWF (Dako; 1:6,400), respectively.…”

Cross-species Proteomics Reveals Specific Modulation of Signaling in Cancer and Stromal Cells by Phosphoinositide 3-kinase (PI3K) Inhibitors

“…In addition to their expression and extent of post-translational modification, the activity of protein kinases can be modulated by allosteric mechanisms regulated by protein-protein interactions. For example, the activity of CK2 is modulated by the ratio of catalytic (alpha) to regulatory (beta) subunits as the latter binds and inactivates the catalytic activity of CK2 alpha (36,38). We found that this ratio of CK2 catalytic to regulatory subunit was modulated by in vivo growth conditions (Fig.…”

“…4A). This is an interesting observation, as it is known that CK2 activity is regulated by the ratio between the alpha and beta subunits (35)(36)(37) in addition to its absolute expression (38,39). CK2 beta binds to CK2 alpha, resulting in the formation of an inactive polymeric complex; thus, an alteration in CK2 subunit ratios (Fig.…”