Regulation of taurine homeostasis by protein kinase CK2 in mouse fibroblasts

Abstract

Increased expression of the ubiquitous serine/threonine protein kinase CK2 has been associated with increased proliferative capacity and increased resistance towards apoptosis. Taurine is the primary organic osmolyte involved in cell volume control in mammalian cells, and shift in cell volume is a critical step in cell proliferation, differentiation and induction of apoptosis. In the present study, we use mouse NIH3T3 fibroblasts and Ehrlich Lettré ascites tumour cells with different CK2 expression levels. Taurine uptake via the Na(+) dependent transporter TauT and taurine release are increased and reduced, respectively, following pharmacological CK2 inhibition. The effect of CK2 inhibition on TauT involves modulation of transport kinetics, whereas the effect on the taurine release pathway involves reduction in the open-probability of the efflux pathway. Stimulation of PLA(2) activity, exposure to exogenous reactive oxygen species as well as inhibition of protein tyrosine phosphotases (PTP) potentiate the swelling-induced taurine loss. Inhibition of PI3K and PTEN reduces and potentiates swelling-induced taurine release, respectively. Inhibition of CK2 has no effect on PLA(2) activity and ROS production by NADPH oxidase, whereas it lifts the effect of PTEN and PTP inhibition. It is suggested that CK2 regulates the taurine release downstream to known swelling-induced signal transducers including PLA(2), NADPH oxidase and PI3K.

Regulation of Taurine Transport Systems by Protein Kinase CK2 in Mammalian Cells

“…Furthermore, inhibition of CK2 also results in decreased activity of the swelling induced taurine release pathway (Fig. 2) [18]. As the effect of CK2 inhibition on taurine transport was similar in the two cell lines it was suggested that CK2 suppresses taurine accumulation regardless to the CK2 expression level.…”

“…Previous reports have introduced the serine/threonine kinase CK2 as a regulator of the active taurine uptake and the passive taurine release [18,19]. CK2 is constitutively active and upregulated in most types of cancers as well as growth stimulated cells where it stimulates proliferation and suppresses apoptosis [20] (see [21]).…”

Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

“…Cellular taurine content is generally a balance between active uptake via the Na ϩ -and Cl Ϫ -dependent taurine transporter (TauT), passive release via volume-sensitive and volume-insensitive transporters (28), and in some cells (liver, pancreas, and testis) synthesis from cystein/methionine (31). Acute modulation of TauT activity involves Ser/Thr kinases (PKA, PKC, and CK2) and reactive oxygen species (ROS) (12,13,22,31,40,41,63), whereas long-term regulation of TauT activity involves transcriptional regulation by cellular osmo-sensing proteins (TonEBP, tonicity end-binding protein) and amino-sensing kinases (mTOR, mammalian target of rapamycin) (9,27,30,31). In contrast to the active taurine uptake system involving TauT, taurine release involves 1) volume-sensitive leak pathways, activated by osmotic cell swelling [termed the volumesensitive organic anion channel (VSOAC)]; and 2) volumeinsensitive leak pathways, activated during anoxia, apoptosis, and cholesterol depletion (27,31,45,61).…”

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

“…The total body pool is controlled by renal taurine retention via TauT located at the proximal tubule and distal nephron. Translocation of one taurine molecule across the plasma membrane via TauT involves two to three Na ions and acute modulation of TauT activity by protein kinases (PKA, PKC, CK2) and ROS involves shift in TauT's substrate affinity, transport capacity, and/or the Na:taurine stoichiometry (13,14,19,45,69). Passive taurine release from cells via VSOAC activation involves 1) mobilization of arachidonic acid from the nuclear envelope by cell-specific PLA 2 subtypes (52,53), ROS generation by NADPH oxidases (8,34), and fatty acid oxidation to leukotrienes by 5-lipoxygenase (5-LO) (38); 2) increased tyrosine kinase activity (34,51); and 3) activation of protein kinases normally related to growth factor signaling, i.e., phosphatidylinositol 3-kinase (PI3K), Akt, and glycogen synthase kinase 3␤ (GSK3␤) (36).…”