The multiple personalities of the regulatory subunit of protein kinase CK2: CK2 dependent and CK2 independent roles reveal a secret identity for CK2beta

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 CK2alpha or CK2alpha' subunits and two regulatory CK2beta 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 CK2beta 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 CK2beta in the absence of catalytic CK2 subunits reinforces the notion that CK2beta has functions distinct from CK2 and begins to offer insights into these CK2-independent functions. In this respect, the discovery that CK2beta 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 CK2beta and these protein kinases with special emphasis on the properties of CK2beta that mediate these interactions and on the implications of these interactions in yielding new prospects for elucidation of the cellular functions of CK2beta.

Figure 1

CK2β: The regulatory subunit of CK2 A. High-resolution crystal structure of the CK2 holoenzyme. The catalytic subunits are represented as an alpha carbon trace (grey) while the CK2β dimer forming the core of the enzyme is represented by blue ribbons. Important motifs are coloured as indicated in the schematic diagram (B). CK2β monomers are distinguished by different shades of the appropriate colour. (prepared using Swiss PDB Viewer; 1JWH 116, 117, 50 ) B. Schematic illustration of CK2β depicting important regions. The phosphorylation sites are represented by black spheres; while the KEN box (orange) and D box (yellow) represent putative degradation motifs. The acidic loop is involved in modulation of catalytic subunit activity by mediating polyamine binding. Cysteines 109, 114, 137 and 140 of the zinc-finger region mediate CK2β dimer formation and the positive regulatory region mediates binding between CK2β and the catalytic subunits. (adapted from 3 )

Figure 2

Sequence alignment of serine/threonine protein kinases containing a putative CK2β binding domain: Comparison of the CK2β binding region of the CK2 catalytic subunits (α and α') with the putative CK2β binding regions identified in other serine/threonine protein kinases, namely Chk1 (aa1-87), c-Mos (aa52-115) and A-Raf (aa323-373). Basic residues – black, acidic residues – blue, small or hydrophobic residues – red, remaining residues - green. Invariant residues are highlighted in yellow while other highly conserved residues are marked by an asterisk (*).

Figure 3

Structural comparison of the CK2β binding regions of CK2α and Chk1. A. Crystal structure depicting the interaction between CK2α (grey and green) and CK2β (blue). The CK2β binding region of CK2α is represented by the green ribbon. CK2β is shown for context. (1JWH 50 ) B. Crystal structure of Chk1 (1IA8 ). The putative CK2β binding region of Chk1 is represented as a red ribbon. Residues that are absolutely conserved between the two CK2β binding regions are shown in black. C. Alignment of the high resolution crystal structures of the CK2β binding regions of tetrameric CK2α (green), CK2α alone (purple; 1PJK 118 ) and Chk1 (red). A backbone representation of the CK2β binding domain of each protein is shown. The amino acid side chains of invariant residues are shown in black. In particular, L11 in Chk1 is analogous to L41 in CK2α and may be important in mediating binding to CK2β.