ArticleMolecular pharmacology2012
Casein kinase 2α regulates multidrug resistance-associated protein 1 function via phosphorylation of Thr249.
Article in Molecular pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 38 citations in OpenAlex.
- Multi-State Structural Genomics Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases.International journal of molecular sciences · 2026Article
- Drug-Induced Liver Injury Associated With Emerging Cancer Therapies.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.Nature communications · 2024Article
- Inhibition of casein kinase 2 induces cell death in tyrosine kinase inhibitor resistant chronic myelogenous leukemia cells.PloS one · 2023Article
- The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation.Nature communications · 2022Article
- Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease.Nature communications · 2021Article
- Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory region of ABCC transporters.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Role of protein kinase CK2 in antitumor drug resistance.Journal of experimental & clinical cancer research : CR · 2019Review
- Post-translational modifications of transporters.Pharmacology & therapeutics · 2018Review
- Beyond Competitive Inhibition: Regulation of ABC Transporters by Kinases and Protein-Protein Interactions as Potential Mechanisms of Drug-Drug Interactions.Drug metabolism and disposition: the biological fate of chemicals · 2018Review
- Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance.Genome biology · 2017Article
- Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression.The Journal of biological chemistry · 2015Article
- Leukemia and ABC transporters.Advances in cancer research · 2015Review
- Cell-permeable dual inhibitors of protein kinases CK2 and PIM-1: structural features and pharmacological potential.Cellular and molecular life sciences : CMLS · 2014Article
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
We have shown previously that the function of Ycf1p, yeast ortholog of multidrug resistance-associated protein 1 (MRP1), is regulated by yeast casein kinase 2α (Cka1p) via phosphorylation at Ser251. In this study, we explored whether casein kinase 2α (CK2α), the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semiconserved site Thr249. Knockdown of CK2α in MCF7-derived cells expressing MRP1 [MRP1 CK2α(-)] resulted in increased doxorubicin sensitivity. MRP1-dependent transport of leukotriene C(4) and estradiol-17β-d-glucuronide into vesicles derived from MRP1 CK2α(-) cells was decreased compared with MRP1 vesicles. Moreover, mutation of Thr249 to alanine (MRP1-T249A) also resulted in decreased MRP1-dependent transport, whereas a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings, showing increased intracellular doxorubicin accumulation in MRP1 CK2α(-) and MRP1-T249A cells compared with MRP1 cells. Inhibition of CK2 kinase by 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2α(-), MRP1-T249A, or MRP1-T249E cells, suggesting that CK2α regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2α and MRP1 interact physically, and recombinant CK2 phosphorylates MRP1-derived peptide in vitro in a Thr249-dependent manner, whereas knockdown of CK2α results in decreased phosphorylation at MRP1-Thr249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin and increased doxorubicin cytotoxicity. This study supports a model in which CK2α potentiates MRP1 function via direct phosphorylation of Thr249.
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