Casein kinase 2 as a potentially important enzyme in the nervous system

Blanquet, P

doi:10.1016/s0301-0082(99)00026-x

Cited by 154 publications

(147 citation statements)

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“…The regulation of CK2 activity is not very well known: change in ratio of a to b subunits as well as in subcellular localization may play a role. 55 Hypoxia did indeed increase the expression of the b subunit and induced a relocalization of this subunit to the plasma membrane. In addition, CK2a translocation into the nucleus was observed.…”

Section: Discussionmentioning

confidence: 91%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Section: Discussionmentioning

confidence: 91%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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“…Protein kinase CK2 is a Ser/Thr kinase ubiquitously expressed in vertebrate tissues with particularly high levels in brain (37,38) where CAPS is also most highly expressed (2,39,40). Numerous CK2 substrates have been suggested to function in synaptic transmission and synaptic plasticity (37).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous CK2 substrates have been suggested to function in synaptic transmission and synaptic plasticity (37). Proteins required for Ca 2ϩ -dependent vesicle exocytosis such as synaptotagmin-1, syntaxin 1A, and VAMP-2 are in vitro substrates of CK2 (12,14,41).…”

Section: Discussionmentioning

confidence: 99%

CAPS Activity in Priming Vesicle Exocytosis Requires CK2 Phosphorylation

Nojiri

Loyet²,

Klenchin

et al. 2009

Journal of Biological Chemistry

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CAPS (Ca 2؉ -dependent activator protein for secretion) functions in priming Ca 2؉ -dependent vesicle exocytosis, but the regulation of CAPS activity has not been characterized. Here we show that phosphorylation by protein kinase CK2 is required for CAPS activity. Dephosphorylation eliminated CAPS activity in reconstituting Ca 2؉ -dependent vesicle exocytosis in permeable and intact PC12 cells. Ser-5, -6, and -7 and Ser-1281 were identified by mass spectrometry as the major phosphorylation sites in the 1289 residue protein. Ser-5, -6, and -7 but not Ser-1281 to Ala substitutions abolished CAPS activity. Protein kinase CK2 phosphorylated CAPS in vitro at these sites and restored the activity of dephosphorylated CAPS. CK2 is the likely in vivo CAPS protein kinase based on inhibition of phosphorylation by tetrabromo-2-benzotriazole in PC12 cells and by the identity of in vivo and in vitro phosphorylation sites. CAPS phosphorylation by CK2 was constitutive, but the elevation of Ca 2؉ in synaptosomes increased CAPS Ser-5 and -6 dephosphorylation, which terminates CAPS activity. These results identify a functionally important N-terminal phosphorylation site that regulates CAPS activity in priming vesicle exocytosis.Regulated neurotransmitter secretion is central to intercellular communication in the nervous system. Two types of secretory vesicles mediate neurotransmitter release; that is, synaptic vesicles that release transmitters such as glutamate at synapses and dense-core vesicles that release modulatory transmitters and neuropeptides at non-synaptic sites. Both types of secretory vesicles are recruited to docking sites on the plasma membrane where they are primed to a ready release state to undergo fusion in response to Ca 2ϩ elevations. Many of the proteins that mediate the targeting, docking, priming, and Ca 2ϩ -dependent fusion of vesicles with the plasma membrane function in both synaptic vesicle and dense-core vesicle pathways (1). CAPS-1 2 (also known as Cadps1) is a 1289-residue protein that reconstitutes Ca 2ϩ -triggered dense-core vesicle exocytosis in permeable neuroendocrine cells at a priming step (2-4). CAPS is required for secretion of a subset of transmitters in Caenorhabditis elegans (5) and Drosophila melanogaster (6) and for priming dense-core vesicle exocytosis in neuroendocrine cells (7) and synaptic vesicle exocytosis in neurons (8). Vesicle priming reactions are extensively modulated during physiological demand (9), but mechanisms that regulate CAPS function remain to be identified.Reversible protein phosphorylation is a major mechanism for the regulation of cellular processes including vesicle exocytosis. Many proteins that function in evoked vesicle exocytosis are phosphoproteins (10, 11). The neuronal SNARE proteins syntaxin 1A, VAMP-2, and SNAP-25 are phosphorylated by several protein kinases in vitro (12)(13)(14). Protein kinase C and protein kinase A sites on SNAP-25 affect refilling rates and size, respectively, of the primed pool of vesicles in chromaffin cells (15,16). Several SNARE...

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“…It is noteworthy that CK2 is also widely exploited by infectious agents, such as viruses and parasites, to perform the phosphorylation of proteins essential to their life cycle [29]. Although CK2 is almost ubiquitous, it is especially abundant in the brain [30], where it is present in all the regions studied [31]. It is therefore conceivable that PrP c and CK2 are given the opportunity to come into contact, especially considering that CK2 is one of the few protein kinases whose presence on the outer leaflet of the plasma membrane, where PrP c also resides, has been demonstrated unambiguously [32].…”

Section: Discussionmentioning

confidence: 99%

Bovine prion protein as a modulator of protein kinase CK2

Meggio

Negro

Sarno

et al. 2000

Biochemical Journal

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On the basis of far-Western blot and plasmon resonance (BIAcore) experiments, we show here that recombinant bovine prion protein (bPrP) (25-242) strongly interacts with the catalytic α\αh subunits of protein kinase CK2 (also termed ' casein kinase 2 '). This association leads to increased phosphotransferase activity of CK2α, tested on calmodulin or specific peptides as substrate. We also show that bPrP counteracts the inhibition of calmodulin phosphorylation promoted by the regulatory β subunits of CK2. A truncated form of bPrP encompassing the Cterminal domain (residues 105-242) interacts with CK2 but does

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Casein kinase 2 as a potentially important enzyme in the nervous system

Cited by 154 publications

References 348 publications

Role for casein kinase 2 in the regulation of HIF‐1 activity

Role for casein kinase 2 in the regulation of HIF‐1 activity

CAPS Activity in Priming Vesicle Exocytosis Requires CK2 Phosphorylation

Bovine prion protein as a modulator of protein kinase CK2

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