Phosphorylation of the regulatory β‐subunit of protein kinase CK2 by checkpoint kinase Chk1: identification of the in vitro CK2β phosphorylation site

Kristensen, Lars; Larsen, Martin R.; Højrup, Peter; Issinger, Olaf‐Georg; Guerra, Bárbara

doi:10.1016/j.febslet.2004.05.069

Cited by 20 publications

(11 citation statements)

References 23 publications

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“…CK2␤ specifically interacts with ALK-1, and CK2␤ has been reported to be phosphorylated by other interacting serine/threonine kinases, including CK2␣ (37) and Chk1 (38). In addition, the interaction of CK2␤ with ALK-1 has the potential to result in the phosphorylation of ALK-1 by other CK2␤-associated serine/threonine kinases.…”

Section: Ck2␤ Enhances Alk-1 Signalingmentioning

confidence: 99%

Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

et al. 2009

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ALK-1 is a transforming growth factor beta (TGF-beta) superfamily receptor that is predominantly expressed in endothelial cells and is essential for angiogenesis, as demonstrated by the embryonic lethal phentoype when targeted for deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia. Although ALK-1 and the endothelial-specific TGF-beta superfamily coreceptor, endoglin, form a heteromeric complex and bind similar TGF-beta superfamily ligands, their signaling mechanisms remain poorly characterized. Here we report the identification of CK2beta, the regulatory subunit of protein kinase CK2, as a novel enhancer of ALK-1 signaling. The cytoplasmic domain of ALK-1 specifically binds to CK2beta in vitro and in vivo. NAAIRS mutagenesis studies define amino acid sequences 181-199 of CK2beta and 207-212 of ALK-1 as the interaction domains, respectively. The ALK-1/CK2beta interaction specifically enhanced Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation in response to TGF-beta1 and BMP-9 treatment. In a reciprocal manner, siRNA-mediated silencing of endogenous CK2beta inhibited TGF-beta1 and BMP-9-stimulated Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation. Functionally, CK2beta enhanced the ability of activated or ligand-stimulated ALK-1 to inhibit endothelial cell migration. Similarly, ALK-1 and CK2beta antagonized endothelial tubule formation in Matrigel. These studies support CK2beta as an important regulator of ALK-1 signaling and ALK-1-mediated functions in endothelial cells.

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Section: Ck2␤ Enhances Alk-1 Signalingmentioning

confidence: 99%

Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

et al. 2009

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“…The constructs encoding for full-length CK2ß (CK2ß-MycHis) and full-length Chk1 (HA-Chk1) were as described previously (8). The kinaseinactive mutant of Chk1 (HA-Chk1KD) was generated as described previously (19). Human CDC25C-MycHis was generated by the polymerase chain reaction (PCR) using the following primers: 5'-CCCAAGCTTGATGTCTACGGACT CTTCTCA-3' (sense) and 5'-CCGCTCGAGCTGGGCTCAT GTCCTTCACCAG-3' (antisense).…”

Section: Immunoprecipitation Antibodies and Western Blot Analysismentioning

confidence: 99%

The regulatory β-subunit of protein kinase CK2 accelerates the degradation of CDC25A phosphatase through the checkpoint kinase Chk1

Kreutzer

Guerra²

2007

Int J Oncol

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Human CDC25 phosphatases play an important role in cell cycle regulation by removing inhibitory phosphate groups on cyclin-CDKs. Chk1 has been shown to phosphorylate CDC25 family members down-regulating their phosphatase activity through distinct mechanisms. The kinase activity of Chk1 is evident in unperturbed cells and becomes enhanced in response to DNA damage or stalled replication. We have previously shown that the activity of Chk1 is increased following interaction with the regulatory ß-subunit of protein kinase CK2. In the present study, ectopic expression of CK2ß during normal cell cycle progression is shown to enhance CDC25A degradation, and this occurs in a manner similar to that by which CDC25A is down-regulated upon activation of cellular checkpoint responses. By using RNA interference to specifically deplete cells of Chk1, we demonstrate that Chk1 mediates the down-regulation of endogenous CDC25A, which occurs upon induction of CK2ß expression. When degradation of CDC25A is induced by CK2ß during activation of the G2 checkpoint, it leads to partial dephosphorylation of Cdc2 at its inhibitory residue Tyr15. These results suggest that protein kinase CK2 is involved in cell cycle regulation and indicate the mechanism by which CDC25A turnover might be regulated by Chk1 in the absence of DNA damage.

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“…1), was identified with missense mutations in our sample. CSNK2B expresses the regulatory beta subunit of casein kinase 2 (CK2) 49-51 - a negative regulator of caspase activity and involved in phosphorylating several substrates that regulate the cell cycle 52. Cell survival is enhanced by both CSNK2B gain-of-function mutations and loss of function mutation in EPHA7 through the inhibition of apoptosis .…”

Section: Resultsmentioning

confidence: 99%

Decoding Somatic Driver Gene Mutations and Affected Signaling Pathways in Human Medulloblastoma Subgroups

Robbins¹,

Bou‐Dargham²,

Sanchez³

et al. 2018

J. Cancer

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Medulloblastoma is the most common malignant pediatric brain tumor. Prior studies have concentrated their efforts studying the four molecular subgroups: SHH, Wnt, group 3, and group 4. SHH and Wnt are driven by their canonical pathways. Groups 3 and 4 are highly metastatic and associated with aberrations in epigenetic regulators. Recent developments in the field have revealed that these subgroups are not as homogenous as previously believed. The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signaling is activated in the SHH subgroup, however, we determined gain-of-function mutations in ubiquitin ligase (CUL1) that inhibit Gli-mediated transcription. This suggests a potential hindrance in SHH signaling for some patients. For group 3, gain-of-function in the inhibitor of proinflammatory cytokines (HIVEP3) suggests an immunosuppressive phenotype and thus a more hostile tumor microenvironment. Surprisingly, group 4 tumors possess mutations that may prompt the activation of Wnt signaling through gain-of-function mutations in MUC16 and PCDH9. These infrequent mutations detected in this study could be due to subclonal or spatially restricted alterations. The investigation of aberrant driver gene mutations can lead to the identification of new drug targets and a greater understanding of human medulloblastoma heterogeneity.

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Phosphorylation of the regulatory β‐subunit of protein kinase CK2 by checkpoint kinase Chk1: identification of the in vitro CK2β phosphorylation site

Cited by 20 publications

References 23 publications

Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

The regulatory β-subunit of protein kinase CK2 accelerates the degradation of CDC25A phosphatase through the checkpoint kinase Chk1

Decoding Somatic Driver Gene Mutations and Affected Signaling Pathways in Human Medulloblastoma Subgroups

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