CK2 Regulation: Perspectives in 2021

Abstract

The protein kinase CK2 (CK2) family encompasses a small number of acidophilic serine/threonine kinases that phosphorylate substrates involved in numerous biological processes including apoptosis, cell proliferation, and the DNA damage response. CK2 has also been implicated in many human malignancies and other disorders including Alzheimer′s and Parkinson’s diseases, and COVID-19. Interestingly, no single mechanism describes how CK2 is regulated, including activation by external proteins or domains, phosphorylation, or dimerization. Furthermore, the kinase has an elongated activation loop that locks the kinase into an active conformation, leading CK2 to be labelled a constitutively active kinase. This presents an interesting paradox that remains unanswered: how can a constitutively active kinase regulate biological processes that require careful control? Here, we highlight a selection of studies where CK2 activity is regulated at the substrate level, and discuss them based on the regulatory mechanism. Overall, this review describes numerous biological processes where CK2 activity is regulated, highlighting how a constitutively active kinase can still control numerous cellular activities. It is also evident that more research is required to fully elucidate the mechanisms that regulate CK2 and what causes aberrant CK2 signaling in disease.

3’UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

“…p53 activity is stimulated by CK2-mediated phosphorylation on Ser392 (Ser389 in mouse), including causing increased DNA binding of recombinant p53 22,23 , and the phosphorylation-deficient S392A mutant displays impaired tumor suppressor activity 24 . CK2 is an oncogenic kinase 25 that acts as a RAS pathway effector through its re-localization to the perinuclear cytoplasm in transformed cells 20 . We used a p53 anti-p-Ser392 antibody to assess whether this phospho-modification occurs in p53-expressing H1299 cells, where signaling is driven by the endogenous NRAS oncoprotein.…”

Copper Modulates the Catalytic Activity of Protein Kinase CK2

“…Furthermore, the binding of CK2 to other proteins such as fibroblast growth factor, p21, and Lamin A alters CK2 activity and promotes or inhibits the phosphorylation of specific substrates ( Skjerpen et al, 2002 ; Jia et al, 2016 ; Ao et al, 2019 ). However, in general, most of these examples are cell-type- or context-specific, and there is currently no known universal mechanism for the catalytic regulation of CK2 kinase activity ( Roffey & Litchfield, 2021 ).…”

Comparing Two Neurodevelopmental Disorders Linked to CK2: Okur-Chung Neurodevelopmental Syndrome and Poirier-Bienvenu Neurodevelopmental Syndrome—Two Sides of the Same Coin?

“…In the brain, CK2α is more abundant than in other tissues, with a predominance of the α subunit over α’ ( Ceglia et al, 2011 ). CK2 is localized in different cellular compartments, is involved in diverse processes such signal transduction, replication, translation, and metabolism ( Roffey and Litchfield, 2021 ), as well as roles in angiogenesis ( Montenarh, 2014 ), development and differentiation ( Götz and Montenarh, 2017 ), and the immune system ( Hong and Benveniste, 2021 ). Moreover, it is upregulated in many cancers ( Ahmad et al, 2005 ; Ruzzene and Pinna, 2010 ; Rowse et al, 2017 ).…”