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Protein Phosphorylation on Tyrosine Restores BMB Reports Protein phosphorylation on tyrosine restores expression and glycosylation of cyclooxygenase-2 by 2-deoxy-D-glucose-caused endoplasmic reticulum stress in rabbit articular chondrocyte Seon-Mi Yu & Song-Ja Kim* Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 314-701, Korea ever, there have been few studies that examined the regulation 2-deoxy-D-glucose(2DG)-caused endoplasmic reticulum (ER) of COX-2 at post-translational levels. stress inhibits protein phosphorylation at tyrosine residues. It has been previously demonstrated that protein phosphor- However, the accurate regulatory mechanisms, which determine ylation results in an increase in COX-2 at the transcription and the inflammatory response of chondrocytes to ER stress via pro- translation levels, and these results are related to protein kin- tein tyrosine phosphorylation, have not been systematically ase C (PKC) and protein tyrosine kinase (PTK) (3). In addition, evaluated. Thus, in this study, we examined whether protein COX-2 activity has been shown to be modulated at the phosphorylation at tyrosine residues can modulate the expression post-translational level by protein tyrosine phosphorylation (4). and glycosylation of COX-2, which is reduced by 2DG-induced The function of proteins and cellular processes are regulated ER stress. We observed that protein tyrosine phosphatase (PTP) in- by protein phosphorylation at tyrosine residues. The amount of hibitors, sodium orthovanadate (SOV), and phenylarsine oxide protein phosphorylation at tyrosine residues is dependent on (PAO) significantly decreased expression of ER stress inducible the balance between the activities of tyrosine kinase and ty- proteins, glucose-regulated protein 94 (GRP94), and CCAAT/ en- rosine phosphatase (5). The overall levels of protein phosphor- hancer-binding-protein- related gene (GADD153), which was in- ylation at tyrosine residues are low in most cells. Treatment duced by 2DG. In addition, we demonstrated that SOV and PAO with a protein tyrosine phosphatase inhibitor in cells results in noticeably restored the expression and glycosylation of COX-2 af- protein phosphorylation at tyrosine residues in unspecified ter treatment with 2DG. These results suggest that protein phos- proteins that are generally maintained in dephosphorylated phorylation of tyrosine residues plays an important role in the forms. regulation of expression and glycosylation during 2DG-induced The ER is a sub-cellular organelle that is involved in the syn- ER stress in rabbit articular chondrocytes. [BMB reports 2012; thesis of secretary and membrane proteins and lipids respon- 45(5): 317-322] sible for several specialized functions, such as protein folding and translocation (6). Several physiological and pathological conditions, such as glucose starvation, disturbance of intra- 2+ INTRODUCTION cellular stores of Ca , oxidative stress, viral infection, and in- hibition of protein glycosylation, can leads to ER stress (7). To Cyclooxygenases (COXs) are the rate-limiting enzyme in the effectively cope with ER stress, cells initiate two distinct re- biosynthesis of PGs and have been linked to inflammatory dis- sponses in the ER lumen to protect against the accumulation of eases, including rheumatoid arthritis (RA) and osteoarthritis unfolded proteins. The first involves the unfolded protein re- (OA) (1). In arthritis, COX-2 is highly expressed in the chon- sponse (UPR), which increases genes coding chaperones, such drocytes and in the synovial tissue (2). The activity and ex- as GRP78 and GRP94. This increases proper protein folding pression of COX are modulated at the levels of transcription, and inhibits the aggregation of unfolded proteins in the ER (8). post-transcription, and translation during inflammation. How- The second is a profound and transient attenuation of protein synthesis. This response reduces the stress associated with pro- *Corresponding author. Tel: +82-41-850-8507; Fax: +82-41-850- tein folding in the ER (9). Both the unfolded protein response 0927; E-mail: [email protected] and the repression of protein synthesis may lead to cytopro- http://dx.doi.org/10.5483/BMBRep.2012.45.5.317 tection or death, depending on the nature of the stress and the cellular environment (9). ER stress negatively or positively reg- Received 10 November 2011, Revised 14 December 2011, ulates COX-2 expression through a variety of signal pathways Accepted 8 February 2012 in normal or abnormal cells (10). Keyword: Chondrocyte, Cyclooxygenase-2, Glycosylation, Tyrosine 2DG is an analogue of glucose, where the 2-hydroxyl group phosphorylation, 2-deoxy-D-glucose is replaced with hydrogen. It is generally believed to be a cru- Copyright ⓒ 2012 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/li- censes/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Tyrosine phosphorylation affects glycosylation of COX-2 Seon-Mi Yu and Song-Ja Kim cial factor in the ER stress response by inhibiting protein glyco- showed that PP2, a specific inhibitor of Src tyrosine kinase, sylation (11). Our previous studies indicated that the ex- could recover the decrease in COX-2 expression caused by pression and glycosylation of COX-2 were reduced by 2DG-in- 2DG treatment (12). Therefore, in this study, we investigated duced ER stress (12). These results indicated that glucose star- the effect of GN, an inhibitor of tyrosine kinase, and PP2 on vation-mediated ER stress appears to be a central regulator in the 2DG-induced reduction in expression and glycosylation of the expression of COX-2. COX-2. In these experiments, GN, an inhibitor of tyrosine kin- Therefore, we investigated the effects of protein tyrosine ase, did not restore the 2DG-induced reduction in COX-2 ex- phosphorylation on expression and glycosylation during pression (Fig. 1B), indicating that = PP2 and GN had different 2DG-induced ER stress by using inhibitors of PTPs in rabbit ar- effects on COX-2 expression after 2DG treatment. ticular chondrocytes. Consistent with the Western blot data, the RT-PCR results al- so showed that inhibitors of PTPs recovered the transcription RESULTS levels of COX-2 (Fig. 1C). To examine whether the reduced ex- pression and glycosylation of COX-2 by 2DG were regulated COX-2 expression was detected in control cultured chon- by protein phosphorylation on serine or threonine, 2DG treat- drocytes, but was not detected in 2DG-treated cells. However, ed cells were incubated with GN, an inhibitor of protein ty- doublet COX-2 (66-70-KDa; arrowheads) bands were weakly rosine kinase, or OA, an inhibitor of serine/threonine phospha- detected in 2DG-treated cells. Our previous study demon- tase (Fig. 1A). OA and GN treatment did not affect GADD153 strated that doublet bands corresponded to the unglycosylated and GRP94 expression (Fig. 1A). Thus, based on the results of form of COX-2 (12). Addition of 2DG to chondrocytes strongly Western blot analysis and RT-PCR (Fig. 1A and C), the reduced decreased protein phosphorylation at tyrosine residues (Fig. expression and glycosylation of COX-2 by 2DG were not re- 1A). Therefore, we sought to explore whether down-regulation covered by GN and OA, either at the translation or tran- of both COX-2 expression and glycosylation rate by 2DG-in- scription levels. duced ER stress was related to protein phosphorylation at ty- The effect of protein tyrosine phosphorylation on COX-2 ac- rosine residues. To examine this relation, cells were treated tivity was investigated using a PGE2 assay (Fig. 2A). 2DG in- with 2DG for 24 h in the absence or presence of SOV, PAO, duced ER stress inhibited the production of PGE2 and in- GN, or OA (Fig. 1A). hibitors of PTPs, SOV, and PAO increased the production of We first examined the role of protein phosphorylation at ty- PGE2 under these conditions (Fig. 2A). In contrast, GN did not rosine residues on the reduction of expression and glyco- have any effects on PGE2 production when compared to that sylation of COX-2 by 2DG. Cells were treated with 2DG for of 2DG treated chondrocytes. These results indicate that main- 24 h in the absence or presence of SOV, PAO, GN, or OA tenance of protein tyrosine phosphorylation with PTPs in- (Fig. 1A). Inhibition of PTPs with SOV or PAO resulted in in- hibitors recuperated the loss of COX-2 activity caused by creased expression and glycosylation of COX-2, while ex- 2DG, as determined by PGE2 production (Fig. 2A). Taken to- pression of GADD153 and GRP94 were markedly decreased in 2DG treated cells (Fig. 1A). In our previous studies, we Fig. 2. Protein phosphorylation at tyrosine residues modulates PGE2 production and GRP94 expression and restores the reduced Fig. 1. Protein phosphorylation at tyrosine residues recovers the re- COX-2 expression caused by 2DG treatment. (A) Chondrocytes duction in COX-2 expression caused by 2DG treatment. (A, B) were treated or not treated with 5 mM 2DG for 24 h in the ab- Chondrocytes were treated or not treated with 5 mM 2DG for 24 sence or presence of various pharmacological agents (2 μM SOV, h in the absence or presence of various pharmacological agents (2 0.5 μM PAO or 40 μM GN). Levels of cellular and secreted μM SOV, 0.5 μM PAO, 40 μM GN, 5 ng/ml OA, 10 μM PP2). PGE2 were determined using a kit assay. The data represent typi- Protein levels of COX-2, GADD153, GRP94, ptyrosine, pSrc and cal results and average values with standard deviations (SD) from actin were detected by Western blot analysis. The arrow indicates independent experiments are shown. *P ＜ 0.05 compared with expression of the reduced molecular mass of COX-2 (∼66 kDa) fol- untreated cells. (B) Primary chondrocytes were treated or not lowing 2DG treatment.
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