Protein kinase CK2 in development and differentiation

Götz, Claudia; Montenarh, Mathias

doi:10.3892/br.2016.829

Cited by 80 publications

(71 citation statements)

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“…CK2 is involved in fundamental cellular processes (1,10), and the dysregulation of its signaling is associated with a wide spectrum of human diseases (2,3). CK2 is also implicated in cell differentiation in various tissues, including skeletal muscle (1,10,11). Skeletal muscle differentiation is an irreversible and tightly orchestrated process, initiated by the activity of key transcription factors of the myogenic regulatory factor (MRF) family, such as myogenic differentiation 1 (MyoD) and myogenic factor 5 (Myf-5).…”

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Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

et al. 2019

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Casein kinase 2 (CK2) is a tetrameric protein kinase composed of 2 catalytic (α and α′) and 2 regulatory β subunits. Our study provides the first molecular and cellular characterization of the different CK2 subunits, highlighting their individual roles in skeletal muscle specification and differentiation. Analysis of C2C12 cell knockout for each CK2 subunit reveals that: 1) CK2β is mandatory for the expression of the muscle master regulator myogenic differentiation 1 in proliferating myoblasts, thus controlling both myogenic commitment and subsequent muscle‐specific gene expression and myotube formation; 2) CK2α is involved in the activation of the muscle‐specific gene program; and 3) CK2α′ activity regulates myoblast fusion by mediating plasma membrane translocation of fusogenic proteins essential for membrane coalescence, like myomixer. Accordingly, CK2α′ overexpression in C2C12 cells and in mouse regenerating muscle is sufficient to increase myofiber size and myonuclei content via enhanced satellite cell fusion. Consistent with these results, pharmacological inhibition of CK2 activity substantially blocks the expression of myogenic markers and muscle cell fusion both in vitro in C2C12 and primary myoblasts and in vivo in mouse regenerating muscle and zebrafish development. Overall, our work describes the specific and coordinated functions of CK2 subunits in orchestrating muscle differentiation and fusogenic activity, highlighting CK2 relevance in the physiopathology of skeletal muscle tissue.—Salizzato, V., Zanin, S., Borgo, C., Lidron, E., Salvi, M., Rizzuto, R., Pallafacchina, G., Donella‐Deana, A. Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity. FASEB J. 33, 10648–10667 (2019). http://www.fasebj.org

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Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

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“…In vitro cell experiments have shown that CK2 inhibition results in cell cycle blockage and death [36][37][38][39]. Thus, CK2 has been associated with proliferation, lineage determination and differentiation of various tissues, including skeletal muscle [40].Pax7 locus [17]. In addition, phosphorylation of Brg1 by CK2 correlated with the subunit composition of the mSWI/SNF enzyme complex and its sub-nuclear localization [17].Here we report novel findings about Brg1 phosphorylation by CK2.…”

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CK2-dependent phosphorylation of the Brg1 chromatin remodeling enzyme occurs during mitosis

Padilla‐Benavides

Haokip

Yoon

et al. 2019

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Brg1 (Brahma related gene 1) is one of two mutually exclusive ATPases that can act as the catalytic subunit of mammalian SWI/SNF chromatin remodeling enzymes that facilitate utilization of the DNA in eukaryotic cells. Brg1 is a phospho-protein and its activity is regulated by specific kinases and phosphatases. Previously, we showed that Brg1 interacts with and is phosphorylated by casein kinase 2 (CK2) in a manner that regulates myoblast proliferation.Here we demonstrate that the Brg1-CK2 interaction occurred during mitosis in embryonic somites and in primary myoblasts derived from satellite cells isolated from muscle tissue. The interaction of CK2 activity with Brg1 and the incorporation of a number of other subunits into the mSWI/SNF enzyme complex were independent of CK2 enzymatic activity. CK2-mediated hyperphosphorylation of Brg1 was observed in mitotic cells derived from multiple cell types and organisms, suggesting functional conservation across tissues and species. The mitotically hyperphosphorylated form of Brg1 was localized with soluble chromatin, demonstrating that CK2-mediated phosphorylation of Brg1 is associated with specific partitioning of Brg1 within sub-cellular compartments. Thus CK2 acts a mitotic kinase that regulates Brg1 phosphorylation and sub-cellular localization.function of Brg1 and leads to a block of myogenic differentiation [16]. However, dephosphorylation of Brg1 by the phosphatase, calcineurin, opposes the activity of PKCβ1, allowing chromatin remodeling by Brg1 and initiation of myogenesis [16]. Mutagenesis and unbiased mass spectrometry analyses of Brg1 phosphopeptides in the presence and absence of a calcineurin inhibitor identified calcineurin target sequences, but the mass spectrometry data identified additional Brg1 phosphopeptides that were not responsive to calcineurin inhibition [16]. This suggested that Brg1 is a target of additional signal transduction pathways. Our subsequent studies showed that Brg1 was phosphorylated by casein kinase 2 (CK2), a Serine/Threonine kinase, which promoted myoblast proliferation and survival by regulating subnuclear localization and incorporation of one of two related subunits, BAF155/BAF170, into the enzyme complex [17].CK2 is ubiquitously expressed and functions as a tetramer of two catalytic subunits, CK2α or CK2α', and two CK2β regulatory subunits, and it has more than 300 known substrates [29][30][31].CK2 is required for cell cycle progression, survival, apoptosis, and transcriptional regulation.Knockout mice lacking the CK2α subunit show cardiac and neural tube defects and die during embryogenesis, whereas mice lacking the α' subunit have impaired spermatogenesis [32][33][34].Knockout of the CK2β subunit in mice leads to reduced proliferation during embryogenesis, which is reflected in the small size of the animals at embryonic day 6.5 (E6.5) and resorption at E7.5 [35]. Analyses of a murine conditional knockout model showed that CK2β is essential for viability of embryonic stem cells and primary embryonic fibroblasts [35]. In vitro ...

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“…In yeast these units can each be of two types and are named a1, a2, b1 39 and b2 (Padmanabha et al, 1990) while several other fungi, including M. oryzae, only contain one CKa 40 (Zhang et al, 2019). CK2 have been shown to phosphorylates a large number of proteins (Meggio and 41 Pinna, 2003;Ahmad et al, 2008;Götz and Montenarh, 2016) and seems involved in many cellular 42 processes (Götz and Montenarh, 2016). Interestingly, intrinsically highly disordered SRP40 protein in 43 yeast (homologous to Nopp140; Insect, Drosophila and Nolc1;Mammal, Human) has been shown to 44 become phosphorylated to varying degrees by CK2 with effects on the SRP40 conformation, binding, 45 and aggregation properties with further effects on the diverse functions of the protein (Tantos et al, 46 2013; Na et al, 2018).…”

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Protein interactions of Magnaporthe oryzae protein kinase CK2 and secondary data analysis of a large number of transcriptomes suggest chaperone-like activity is integral to its function

Zhang

Liú

et al. 2019

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19CK2, a serine/threonine (S/T) kinase present in eukaryotic cells is known to have a vast number of 20 substrates. We have recently shown that it localizes to nuclei and at pores between hyphal 21 compartments in M. oryzae. We performed a pulldown-proteomics of M. oryzae CK2 catalytic subunit 22 MoCKa to detect interacting proteins. The MoCKa pulldown was enriched for septa and nucleoli 23 proteins and intrinsically disordered proteins (IDPs) containing a CK2 phosphorylation motif proposed 24 to destabilize and unfold alpha helixes. This points to a function for CK2 phosphorylation and 25 corresponding phosphatase dephosphorylation in the formation of functional protein-protein aggregates 26 and protein-RNA/DNA binding. To test this as widely as possible we used secondary data downloaded 27 2 from databases from a large range of M. oryzae experiments and also for a relatively closely related 28 plant pathogenic fungus, Fusarium graminearum. We found that CKa expression was strongly 29 positively correlated with S/T phosphatases as well as with disaggregase (HSP104, YDJ1, SSA1) and 30 an autophagy indicating protein (ATG8). The latter points to increased protein aggregate formation at 31 high levels of CKa expression. Our results suggest a general role for CK2 in aggregation and 32 disaggregation of IDPs and their binding to proteins, DNA and RNA interactions. 33 34 35 36CK2 is a serine/threonine (S/T) kinase constitutively active in eukaryotes (Meggio and Pinna, 2003). 37The CK2 holoenzyme is a heterotetrameric structure consisting of two α-units and two regulatory β-38 subunits (Ahmad et al., 2008). In yeast these units can each be of two types and are named a1, a2, b1 39 and b2 (Padmanabha et al., 1990) while several other fungi, including M. oryzae, only contain one CKa 40 (Zhang et al., 2019). CK2 have been shown to phosphorylates a large number of proteins (Meggio and 41 Pinna, 2003;Ahmad et al., 2008;Götz and Montenarh, 2016) and seems involved in many cellular 42 processes (Götz and Montenarh, 2016). Interestingly, intrinsically highly disordered SRP40 protein in 43 yeast (homologous to Nopp140; Insect, Drosophila and Nolc1;Mammal, Human) has been shown to 44 become phosphorylated to varying degrees by CK2 with effects on the SRP40 conformation, binding, 45 and aggregation properties with further effects on the diverse functions of the protein (Tantos et al., 46 2013; Na et al., 2018). The large number of substrates of CK2, could possibly be explained if CK2 47To test this destabilization/unfolding hypothesis in a general way we decided to make an analysis of 64 secondary data already published (Smith et al., 2011;Zaritsky, 2018) and downloaded a large range of 65 transcriptomic data for M. oryzae. The following hypotheses resulting from the general hypothesis 66 were tested: Sub-hypothesis 1: If unfolding-refolding activity is important for IDP aggregation then a 67 high CKa expression should be correlated with expression of some S/T phosphatases present in the 68 pulldown that can act as a counte...

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Protein kinase CK2 in development and differentiation

Cited by 80 publications

References 92 publications

Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

CK2-dependent phosphorylation of the Brg1 chromatin remodeling enzyme occurs during mitosis

Protein interactions of Magnaporthe oryzae protein kinase CK2 and secondary data analysis of a large number of transcriptomes suggest chaperone-like activity is integral to its function

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