Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2

Chakraborty, Anutosh; Werner, J. Kent; Koldobskiy, Michael A.; Mustafa, Asif K.; Juluri, Krishna R.; Pietropaoli, Joseph W.; Snowman, Adele M.; Snyder, Solomon H.

doi:10.1073/pnas.1019381108

Cited by 39 publications

(31 citation statements)

References 31 publications

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“…4b). This result shows that InsP 6 K2 is also activated under this condition because InsP 6 K2 is reportedly phosphorylated and degraded by CK2 [18], which leads to a decrease in InsP 6 K2 activity.…”

Section: Insp 6 K2 and Cytoplasmic Tdp-43 Induced Depletion Of Akt Phmentioning

confidence: 84%

“…CK2 phosphorylates TDP-43, alpha-synuclein, and other molecules in a strong manner [43]. InsP 6 K2 is reportedly phosphorylated and degraded by CK2 [18], which leads to a decrease in InsP 6 K2 activity. The hyperphosphorylation of the TDP-43 C-terminal fragment facilitates its disassociation from the aggregate, thereby promoting its degradation by the ubiquitin proteasome system and the removal of its remnants from the cell [44].…”

Section: Discussionmentioning

confidence: 98%

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Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

et al. 2015

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TAR DNA-binding protein 43 (TDP-43) has been identified as a major component of ubiquitin-positive inclusions in the brains and spinal cords of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) or amyotrophic lateral sclerosis (ALS). The phosphorylated C-terminal fragment of TDP-43 forms aggregates in the neuronal cytoplasm, possibly resulting in neuronal cell death in patients with FTLD-U or ALS. The inositol pyrophosphate known as diphosphoinositol pentakisphosphate (InsP7) contains highly energetic pyrophosphate bonds. We previously reported that inositol hexakisphosphate kinase type 2 (InsP6K2), which converts inositol hexakisphosphate (InsP6) to InsP7, mediates cell death in mammalian cells. Moreover, InsP6K2 is translocated from the nucleus to the cytosol during apoptosis. In this study, we verified that phosphorylated TDP-43 co-localized and co-bound with InsP6K2 in the cytoplasm of anterior horn cells of the spinal cord. Furthermore, we verified that cell death was augmented in the presence of cytoplasmic TDP-43 aggregations and activated InsP6K2. However, cells with only cytoplasmic TDP-43 aggregation survived because Akt activity increased. In the presence of both TDP-43 aggregation and activated InsP6K2 in the cytoplasm of cells, the expression levels of HSP90 and casein kinase 2 decreased, as the activity of Akt decreased. These conditions may promote cell death. Thus, InsP6K2 could cause neuronal cell death in patients with FTLD-U or ALS. Moreover, InsP6K2 plays an important role in a novel cell death pathway present in FTLD-U and ALS.

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Section: Insp 6 K2 and Cytoplasmic Tdp-43 Induced Depletion Of Akt Phmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

et al. 2015

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“…CSNK2A1 exerts its anti-apoptotic role by protecting regulatory proteins from caspase-mediated degradation [29]. In addition, this molecule promotes cell survival by activating the Akt and Wnt signaling pathway [30]. The high overexpression exhibited by ARHGDIA and CSNK2A1 makes them potential candidate biomarkers of toxicity.…”

Section: Proteins Involved In Programmed Cell Death (Apoptosis)mentioning

confidence: 99%

Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity

et al. 2012

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Understanding the molecular mechanisms underlying MeHg toxicity and the way in which this molecule interacts with living organisms is a critical point since MeHg represents a well-known risk to ecosystems and human health. We used a quantitative proteomic approach based on stable isotopic labeling by amino acids in cell culture in combination with SDS-PAGE and nanoflow LC-ESI-LTQ for analyzing the differential protein expression of hepatic cells associated to MeHg exposure. Seventy-eight proteins were found de-regulated by more than 1.5-fold. We identified a number of proteins involved in different essential biological processes including apoptosis, mitochondrial dysfunction, cellular trafficking and energy production. Among these proteins, we found several molecules whose de-regulation has been already related to MeHg exposure, thus confirming the usefulness of our discovery approach, and new ones that helped to gain a deeper insight into the biomolecular mechanisms related to MeHg-induced toxicity. Overexpression of several HSPs and the proteasome 26S subunit itself showed the proteasome system as a molecular target of toxic MeHg. As for the interaction networks, the top ranked was the nucleic acid metabolism, where many of the identified de-regulated proteins are involved.

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“…IP 6 is recognized as an important regulator of many cellular functions in animal cells, including signal transduction, cell proliferation, and differentiation (25). Recent study showed that CK2 mediates cell survival through phosphorylation of inositol hexakisphosphate kinase-2 by enhancing its ubiquitination (26). Previously, we have shown that nucleolar phosphoprotein 140 (Nopp140), which is a nucleolar protein, specifically binds to CK2α and inhibits its catalytic activity in vitro (27).…”

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confidence: 99%

Structural and functional insights into the regulation mechanism of CK2 by IP ₆ and the intrinsically disordered protein Nopp140

Lee¹,

Son²,

Jin³

et al. 2013

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

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Protein kinase CK2 is a ubiquitous kinase that can phosphorylate hundreds of cellular proteins and plays important roles in cell growth and development. Deregulation of CK2 is related to a variety of human cancers, and CK2 is regarded as a suppressor of apoptosis; therefore, it is a target of anticancer therapy. Nucleolar phosphoprotein 140 (Nopp140), which is an intrinsically disordered protein, interacts with CK2 and inhibits the latter's catalytic activity in vitro. Interestingly, the catalytic activity of CK2 is recovered in the presence of D-myo-inositol 1,2,3,4,5,6-hexakisphosphate (IP 6 ). IP 6 is widely distributed in animal cells, but the molecular mechanisms that govern its cellular functions in animal cells have not been completely elucidated. In this study, the crystal structure of CK2 in complex with IP 6 showed that the lysine-rich cluster of CK2 plays an important role in binding to IP 6 . The biochemical experiments revealed that a Nopp140 fragment (residues 568-596) and IP 6 competitively bind to the catalytic subunit of CK2 (CK2α), and phospho-Ser574 of Nopp140 significantly enhances its interaction with CK2α. Substitutions of K74E, K76E, and K77E in CK2α significantly reduced the interactions of CK2α with both IP 6 and the Nopp140-derived peptide. Our study gives an insight into the regulation of CK2. In particular, our work suggests that CK2 activity is inhibited by Nopp140 and reactivated by IP 6 by competitive binding at the substrate recognition site of CK2.inositol hexakisphosphate | IDP | phosphorylation P rotein phosphorylation is a major aspect of signaling in cells including cell cycle (1). Casein kinase 2 (CK2) is a ubiquitous protein kinase that is essential for cell growth (2), development, and other essential cellular processes (3-7). More than 300 proteins that are involved in DNA replication, transcription, translation, and signal transduction are phosphorylated by CK2 (8). CK2 is also involved in the regulation of apoptosis (9, 10). CK2-dependent phosphorylation of AKT kinase, which is essential for cell survival, activates cells to resist apoptosis (11,12). In addition, CK2-dependent phosphorylation of β-catenin, which induces cell proliferation by Wnt signaling, increases its stability and ability to resist proteolysis (13). Deregulation of CK2 is strongly related to a variety of human cancers (14-17), and therefore, CK2 is considered a target for anticancer therapy (18).Structural and biochemical studies have revealed the molecular architecture and catalytic mechanism of CK2. CK2 consists of two catalytic subunits (α and α′) and two regulatory subunits (β) which can form α 2 β 2 or αα′β 2 heterotetramers (19). The crystal structure of the CK2 holoenzyme is composed of a central dimer of regulatory subunits with catalytic subunits bound to them (20). The active site and residues that are critical for substrate binding have been identified (21). The structure of CK2α in complex with an ATP-analog inhibitor showed a common ATP binding pocket that consists of the residues Lys68,...

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Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2

Cited by 39 publications

References 31 publications

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity

Structural and functional insights into the regulation mechanism of CK2 by IP ₆ and the intrinsically disordered protein Nopp140

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Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2

Cited by 39 publications

References 31 publications

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

Inositol Hexakisphosphate Kinase 2 Promotes Cell Death in Cells with Cytoplasmic TDP-43 Aggregation

Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity

Structural and functional insights into the regulation mechanism of CK2 by IP 6 and the intrinsically disordered protein Nopp140

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Structural and functional insights into the regulation mechanism of CK2 by IP ₆ and the intrinsically disordered protein Nopp140