Protein Kinase CK2 is a Constitutively Active Enzyme that Promotes Cell Survival: Strategies to Identify CK2 Substrates and Manipulate its Activity in Mammalian Cells

Turowec, Jacob P.; Duncan, James S.; French, Ashley C; Gyenis, Laszlo; Denis, Nicole A. St.; Vilk, Greg; Litchfield, David W.

doi:10.1016/b978-0-12-381298-8.00023-x

Cited by 69 publications

(63 citation statements)

References 26 publications

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“…There was no fluctuation in S118 phosphorylation (data not shown). This was not surprising in light of the constitutive activity of CK2␣ throughout the cell cycle (60). Our data indicate that serine 118 is dephosphorylated in response to signals such as apoptotic stimuli (e.g., STS and Fas) for subsequent cleavage by caspase 7 (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…CK2 is ubiquitously present in all eukaryotic cells, highly conserved from yeast to humans, and is constitutively active in cells. It is normally present as a tetrameric complex and consists of two catalytic subunits (␣ and/or ␣=) in a homozygous or heterozygous composition and two noncatalytic regulatory (␤) subunits (16,32,37,47,60). There is high CK2 constitutive activity in all cancer types examined.…”

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confidence: 99%

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Phosphorylation of the Transcription Factor YY1 by CK2α Prevents Cleavage by Caspase 7 during Apoptosis

Riman

Rizkallah

Kassardjian

et al. 2012

Molecular and Cellular Biology

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In this report, we describe the phosphorylation of Yin Yang 1 (YY1) in vitro and in vivo by CK2␣ (casein kinase II), a multifunctional serine/threonine protein kinase. YY1 is a ubiquitously expressed multifunctional zinc finger transcription factor implicated in regulation of many cellular and viral genes. The products of these genes are associated with cell growth, the cell cycle, development, and differentiation. Numerous studies have linked YY1 to tumorigenesis and apoptosis. YY1 is a target for cleavage by caspases in vitro and in vivo as well, but very little is known about the mechanisms that regulate its cleavage during apoptosis. Here, we identify serine 118 in the transactivation domain of YY1 as the site of CK2␣ phosphorylation, proximal to a caspase 7 cleavage site. CK2␣ inhibitors, as well as knockdown of CK2␣ by small interfering RNA, reduce S118 phosphorylation in vivo and enhance YY1 cleavage under apoptotic conditions, whereas increased CK2␣ activity by overexpression in vivo elevates S118 phosphorylation. A serine-to-alanine substitution at serine 118 also increases the cleavage of YY1 during apoptosis compared to wild-type YY1. Taken together, we have discovered a regulatory link between YY1 phosphorylation at serine 118 and regulation of its cleavage during programmed cell death.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

Phosphorylation of the Transcription Factor YY1 by CK2α Prevents Cleavage by Caspase 7 during Apoptosis

Riman

Rizkallah

Kassardjian

et al. 2012

Molecular and Cellular Biology

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“…Moreover, the CK2 holoenzyme is constitutively active (28), suggesting that the subcellular localization and binding partners of CK2 are the primary determining factor in its substratetargeting capacity. To investigate the functional interplay between Pax7 and CK2, we performed proximity ligation assay (PLA) on primary myoblasts during a differentiation time course.…”

Section: Phosphorylation Of Pax7 Via Ck2 Prevents Caspase 3 Cleavage Andmentioning

confidence: 99%

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

Dick

Chang

Dumont

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC selfrenewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.caspase | satellite cells | Pax7 | casein kinase 2 | self-renewal

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“…S1PR1, S1PR2 and TPaR were obtained from Missouri S&T complementary DNA resource centre. CK2 plasmid was obtained from David Litchfield (University of Western Ontario) via Addgene and has been described previously 53 . AT1AR and M1MR have been described previously 55 .…”

Section: Methodsmentioning

confidence: 99%

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

et al. 2014

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Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure-function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G proteincoupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

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Protein Kinase CK2 is a Constitutively Active Enzyme that Promotes Cell Survival: Strategies to Identify CK2 Substrates and Manipulate its Activity in Mammalian Cells

Cited by 69 publications

References 26 publications

Phosphorylation of the Transcription Factor YY1 by CK2α Prevents Cleavage by Caspase 7 during Apoptosis

Phosphorylation of the Transcription Factor YY1 by CK2α Prevents Cleavage by Caspase 7 during Apoptosis

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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