The cyclin H/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylation of cyclin H

Schneider, Eberhard; Kartarius, Sabine; Schuster, Norbert; Montenarh, Mathias

doi:10.1038/sj.onc.1205690

Cited by 35 publications

(30 citation statements)

References 29 publications

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“…Similar to RNSP1, here we showed that an inhibition of the hPrp3p phosphorylation also leads to an inhibition of the splicing. Several proteins, which are implicated in transcription and posttranscriptional processes are substrates for protein kinase CK2 including RNA polymerase II (Payne et al, 1989), cyclin H (Schneider et al, 2002) and FCP1 (TFIIF-dependent CTD phosphatase) (Trembley et al, 2003). Interestingly, RNPS1 also interacts with the largest subunit of RNA polymerase II.…”

Section: Discussionmentioning

confidence: 99%

“…Among the more than 300 substrates discovered to this date, are a lot of proteins that are implicated in cell cycle control, DNA replication/repair, proliferation and transcription/translation (Meggio and Pinna, 2003). The C-terminal domain (CTD) of the largest RNA polymerase II subunit (Cabrejos et al, 2004), the TFIIF-dependent CTD phosphatase 1 (FCP1) (Palancade et al, 2002) and cyclin H (Faust et al, 2002;Schneider et al, 2002;Krempler et al, 2005) belong to the substrates that are known to regulate transcriptional events. Cyclin H is phosphorylated at threonine 315 by CK2 and this phosphorylation is needed for full activity of the cdk7/ cyclin H/Mat1 complex towards a CTD peptide of RNA polymerase II.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase CK2 interacts with the splicing factor hPrp3p

et al. 2007

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Numerous signalling pathways in cells are influenced by the ubiquitous Ser/Thr protein kinase CK2. Protein kinase CK2 is composed of two regulatory b-subunits and two catalytic a-or a 0 -subunits. Several of the known CK2 substrates are proteins known to regulate transcriptional events. Here, we describe that protein kinase CK2 interacts with the splicing factor hPrp3p, which is important for the assembly of the spliceosome. In a twohybrid screen hPrp3p is exclusively bound to the catalytic a-or a 0 -subunits of CK2 but not to the regulatory bsubunit. The interaction was confirmed by coimmunoprecipitation experiments in vitro and in vivo. Moreover, both proteins colocalized in nuclear speckles which is typical for splicing factor compartments within the nucleus. Phosphorylation experiments revealed that hPrp3p is also a substrate of protein kinase CK2. The main phosphorylation site was mapped to C-terminal residues. In vitro and in vivo splicing assays showed that the splicing activity is significantly influenced by the CK2-hPrp3p interaction. Thus, these data showed that CK2 is involved in the regulation of RNA processing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein kinase CK2 interacts with the splicing factor hPrp3p

et al. 2007

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“…Today, CK2 is known to phosphorylate more than 300 cellular and viral proteins, and yet the list is far from complete, as shown by comparative amino acid sequence screen analyses among putative CK2 phosphorylation motifs/sites (36,53). Among these substrates are proteins involved in DNA replication (topoisomerase I [36,44]), transcription (c-Myc [36,44]), cell cycle control (cyclin H [55]), ribosome biogenesis (L5 [42]), apoptosis induction (Bid [14]), and cell differentiation (HOXB7 [71]), as well as numerous viral proteins (e.g., EB2 from Epstein-Barr virus [[EBV] [35], EBNA-2 from EBV [24], NS2 from hepatitis C virus [HCV] [21], and ZEBRA from EBV [17]), that comprise ca. 10% of the known CK2 substrates (36).…”

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confidence: 99%

The Human Adenovirus Type 5 E1B 55-Kilodalton Protein Is Phosphorylated by Protein Kinase CK2

Ching

Dobner

Koyuncu

2012

J Virol

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The human adenovirus type 5 (HAdV5) early region 1B 55-kDa protein (E1B-55K) is a multifunctional phosphoprotein playing several critical roles during adenoviral productive infection, e.g., degradation of host cell proteins, viral late mRNA export, and inhibition of p53-mediated transcription. Many of these functions are apparently regulated at least in part by the phosphorylation of E1B-55K occurring at a stretch of amino acids resembling a potential CK2 consensus phosphorylation motif. We therefore investigated the potential role of CK2 phosphorylation upon E1B-55K during adenoviral infection. A phosphonegative E1B-55K mutant showed severely reduced virus progeny production, although viral early, late, and structural protein levels and viral DNA replication were not obviously affected. Binding studies revealed an interaction between the CK2␣ catalytic subunit and wild-type E1B-55K, which is severely impaired in the phosphonegative E1B mutant. In addition, in situ the ␣-catalytic subunit is redistributed into ring-like structures surrounding E1B-55K nuclear areas and distinct cytoplasmic accumulations, where a significant amount of CK2␣ colocalizes with E1B-55K. Furthermore, in in vitro phosphorylation assays, wild-type E1B-55K glutathione S-transferase fusion proteins were readily phosphorylated by the CK2␣ subunit but inefficiently phosphorylated by the CK2 holoenzyme. Addition of the CK2-specific inhibitors TBB (4,5,6,7-tetrabromobenzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) to infected cells confirmed that CK2␣ binding to E1B-55K is necessary for efficient phosphorylation of E1B-55K. In summary, our data show that CK2␣ interacts with and phosphorylates HAdV5 E1B-55K at residues S490/491 and T495 and that these posttranslational modifications are essential for E1B-55K lytic functions.T he cellular CK2 protein is a serine/threonine kinase known to be ubiquitously expressed, highly conserved in eukaryotic cells, and considered to be constitutively active (36,46,62). Today, CK2 is known to phosphorylate more than 300 cellular and viral proteins, and yet the list is far from complete, as shown by comparative amino acid sequence screen analyses among putative CK2 phosphorylation motifs/sites (36,53 (36). Apart from its role in normal cellular signaling pathways and viral infections, CK2 is reported to be involved in tumorigenesis. For example, increased CK2 activity is linked to several kinds of malignancies such as breast cancer (31, 38) or colorectal carcinoma (47), while reduced activity has been associated with limited cell viability (60,66,68). Indeed, the large number of cellular substrates highlights the important role CK2 plays in maintaining cell homeostasis. Several studies have shown that knockout of the CK2␣ or ␤ subunit is lethal at the embryonic stage in mice (10,58,66).CK2␣ or CK2␣= can form homo-or heterodimers and assemble with a homodimer of ␤ subunits to form the CK2 holoenzyme (18,23,46). Either the holoenzyme or ␣ and ␣= subunits show constitutive activity, so ...

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“…Several of the nuclear CK2 substrates are proteins that are known to regulate transcriptional events, including the CTD of the largest RNAP II subunit, cyclin H, and FCP1 (TFIIF-dependent CTD phosphatase 1) (36,45). CK2 phosphorylation of cyclin H is important for full cyclin H/CDK7/ Mat1 kinase activity with a CTD peptide as a substrate (42). In Xenopus laevis cell extracts, CK2 phosphorylation also enhances the phosphatase activity of FCP1 and binding to the RAP74 subunit of TFIIF, thereby promoting sequential transcriptional cycles (35).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we show here that serine residue 53 (Ser-53) of RNPS1 is phosphorylated by casein kinase II (CK2). CK2 phosphorylates several key cell cycle and transcriptional proteins (36,42), interacts with multiple signaling pathways, and is proposed to be an important mediator of cell survival. In contrast to the effect of SR protein kinases on SR proteins, we show that the nuclear localization of RNPS1 is not affected by CK2 phosphorylation.…”

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confidence: 99%

Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation

Trembley¹,

Tatsumi

Sakashita

et al. 2005

Molecular and Cellular Biology

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Human RNPS1 was originally characterized as a pre-mRNA splicing activator in vitro and was shown to regulate alternative splicing in vivo. RNPS1 was also identified as a protein component of the splicingdependent mRNP complex, or exon-exon junction complex (EJC), and a role for RNPS1 in postsplicing processes has been proposed. Here we demonstrate that RNPS1 incorporates into active spliceosomes, enhances the formation of the ATP-dependent A complex, and promotes the generation of both intermediate and final spliced products. RNPS1 is phosphorylated in vivo and interacts with the CK2 (casein kinase II) protein kinase. Serine 53 (Ser-53) of RNPS1 was identified as the major phosphorylation site for CK2 in vitro, and the same site is also phosphorylated in vivo. The phosphorylation status of Ser-53 significantly affects splicing activation in vitro, but it does not perturb the nuclear localization of RNPS1. In vivo experiments indicated that the phosphorylation of RNPS1 at Ser-53 influences the efficiencies of both splicing and translation. We propose that RNPS1 is a splicing regulator whose activator function is controlled in part by CK2 phosphorylation.Results from the human genome project have underscored the critical importance of alternative pre-mRNA splicing for the expression of a full complement of proteins from an unexpectedly small set of genes (14,15,46). Only 20,000 to 25,000 protein-coding genes are estimated to be present in the human genome, but the human proteome is considerably more diverse and complex due to the extensive use of alternative splicing (reviewed in references 11 and 26). Alternative splicing is often precisely regulated in response to tissue-specific, physiologic, or developmental signals (reviewed in references 7, 21, and 49). Gene-specific regulatory elements and their trans-acting factors have been individually studied. However, the general mechanisms of constitutive and alternative splice site selection are still poorly understood. Through research designed to elucidate the basic mechanisms of alternative splice site selection in mammalian cells, members of the SR and hnRNP A/B protein families have been characterized. Proteins from these two families often have antagonistic effects upon splice site selection, i.e., they cause the stimulation of proximal and distal alternative splice sites, respectively (reviewed in reference 3). Members of the SR and hnRNP A/B protein families also promote opposite effects on splicing activation through binding to an exonic splicing enhancer (ESE) and an exonic splicing silencer (ESS), respectively (reviewed in reference 6).Pre-mRNA splicing factors such as the SR proteins localize to 20 to 50 irregularly shaped nuclear speckles (also called splicing factor compartments [SFCs]) and to the nucleoplasm (reviewed in reference 30). Transcription and splicing are generally thought to occur on the periphery of and outside of SFCs, with SR proteins shuttling between SFCs and active sites of transcription and splicing in a phosphorylation-dependent man...

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The cyclin H/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylation of cyclin H

Cited by 35 publications

References 29 publications

Protein kinase CK2 interacts with the splicing factor hPrp3p

Protein kinase CK2 interacts with the splicing factor hPrp3p

The Human Adenovirus Type 5 E1B 55-Kilodalton Protein Is Phosphorylated by Protein Kinase CK2

Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation

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