The Multiple Personalities of the Regulatory Subunit of Protein Kinase CK2: CK2 Dependent and CK2 Independent Roles Reveal a Secret Identity for CK2β

Abstract

Protein kinase CK2 (formerly casein kinase II), an enzyme that participates in a wide variety of cellular processes, has traditionally been classified as a stable tetrameric complex consisting of two catalytic CK2α or CK2α' subunits and two regulatory CK2β subunits. While consideration of CK2 as a tetrameric complex remains relevant, significant evidence has emerged to challenge the view that its individual subunits exist exclusively within these complexes. This review will summarize biochemical and genetic evidence indicating that the regulatory CK2β subunit exists and performs functions independently of CK2 tetramers. For example, unbalanced expression of catalytic and regulatory CK2 subunits has been observed in a variety of tissues and tumors. Furthermore, localization studies including live cell imaging have demonstrated that while the catalytic and regulatory subunits of CK2 exhibit extensive co-localization, independent mobility of the individual CK2 subunits can also be observed within cells. Identification of proteins that interact with CK2β in the absence of catalytic CK2 subunits reinforces the notion that CK2β has functions distinct from CK2 and begins to offer insights into these CK2-independent functions. In this respect, the discovery that CK2β can interact with and modulate the activity of a number of other serine/threonine protein kinases including A-Raf, c-Mos and Chk1 is particularly striking. This review will discuss the interactions between CK2β and these protein kinases with special emphasis on the properties of CK2β that mediate these interactions and on the implications of these interactions in yielding new prospects for elucidation of the cellular functions of CK2β.

p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

“…Moreover, live-cell fluorescent imaging and X-ray crystallography studies (Niefind et al, 2001) have revealed the subcellular dynamics of CK2 subunits and the transient nature of their interaction. These data again support of the notion that at least some aspects of CK2b functions are not based on its interaction with the CK2 catalytic subunit (Filhol et al, 2004;Bibby and Litchfield, 2005). In mice as well as in Caenorhabditis elegans, a functional loss of CK2b is lethal, demonstrating that the protein is essential for viability (Fraser et al, 2000;Buchou et al, 2003).…”

“…Binding of P1 to CK2b may compete for a common binding site on the protein for unknown endogenous ligands that are essential for cell survival. There is mounting evidence that the two CK2 subunits can exist in their free form outside the tetrameric complex (Bibby and Litchfield, 2005;Filhol et al, 2004). For instance, more than 40 different proteins were shown to interact with CK2b, and importantly, this protein was characterized as a regulatory binding partner of several protein kinases involved in cell signalling (Guerra and Issinger, 1999).…”

“…Disruption of CK2b in transgenic mice has revealed the importance of this regulatory protein in the maintenance of cell proliferation and cell viability (Buchou et al, 2003). Thus, the emerging picture is that CK2b not only exerts a tight control over the catalytic activity of CK2 but may also serve as interaction assembly point for different pathway components (Bibby and Litchfield, 2005). In this respect, there are examples of cells in which an alteration in a selected protein that signals inappropriately for entry into the cell cycle is detected by the p53 checkpoint.…”

“…The three-dimensional structure of the CK2b dimer has revealed the presence of solvent-exposed and -conserved residues that may represent binding surfaces for the multiple protein ligands previously identified as CK2b partners (Chantalat et al, 1999;Grein et al, 1999;Filhol et al, 2004). The identification of important protein kinases including A-Raf, c-Mos, Chk1 and Chk2 (Guerra et al, 1999b(Guerra et al, , 2003Bjorling-Poulsen et al, 2005) that interact with CK2b in the absence of catalytic CK2 subunits strongly suggests that CK2b has functions distinct from CK2a (Bibby and Litchfield, 2005). Moreover, live-cell fluorescent imaging and X-ray crystallography studies (Niefind et al, 2001) have revealed the subcellular dynamics of CK2 subunits and the transient nature of their interaction.…”

Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells

“…CK2 appears distributed in tetrameric complexes inside the cells but significant evidence indicates that the individual subunits do not exist exclusively within these complexes but also as free proteins (Litchfield, 2003;Bibby and Litchfield, 2005).…”