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Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma.
J Biol Chem. 2016 08 19; 291(34):17804-15.JB

Abstract

The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the α catalytic subunit (CK2α, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2α protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2α in drug resistance to Food and Drug Administration-approved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2α decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2α sensitized cells to inhibitor treatment. CK2α-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2α post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2α, that RAF-MEK inhibitor resistance did not rely on CK2α kinase catalytic function, and both wild-type and kinase-inactive CK2α maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2α bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2α increases KSR facilitation of ERK phosphorylation. Accordingly, CK2α did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2α that promotes resistance to RAF- and MEK-targeted therapies.

Authors+Show Affiliations

From the Department of Pharmacology.Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.From the Department of Pharmacology, Lineberger Comprehensive Cancer Center, and.From the Department of Pharmacology, Lineberger Comprehensive Cancer Center, and Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599 and adrienne_cox@med.unc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27226552

Citation

Zhou, Bingying, et al. "Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma." The Journal of Biological Chemistry, vol. 291, no. 34, 2016, pp. 17804-15.
Zhou B, Ritt DA, Morrison DK, et al. Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. J Biol Chem. 2016;291(34):17804-15.
Zhou, B., Ritt, D. A., Morrison, D. K., Der, C. J., & Cox, A. D. (2016). Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. The Journal of Biological Chemistry, 291(34), 17804-15. https://doi.org/10.1074/jbc.M115.712885
Zhou B, et al. Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. J Biol Chem. 2016 08 19;291(34):17804-15. PubMed PMID: 27226552.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. AU - Zhou,Bingying, AU - Ritt,Daniel A, AU - Morrison,Deborah K, AU - Der,Channing J, AU - Cox,Adrienne D, Y1 - 2016/05/17/ PY - 2015/12/25/received PY - 2016/5/27/entrez PY - 2016/5/27/pubmed PY - 2017/5/13/medline KW - CK2 KW - Ras protein KW - drug resistance KW - dual specificity phosphoprotein phosphatase KW - extracellular signal-regulated kinase (ERK) KW - kinase suppressor of RAS 1 (KSR1) KW - melanoma SP - 17804 EP - 15 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 291 IS - 34 N2 - The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the α catalytic subunit (CK2α, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2α protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2α in drug resistance to Food and Drug Administration-approved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2α decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2α sensitized cells to inhibitor treatment. CK2α-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2α post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2α, that RAF-MEK inhibitor resistance did not rely on CK2α kinase catalytic function, and both wild-type and kinase-inactive CK2α maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2α bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2α increases KSR facilitation of ERK phosphorylation. Accordingly, CK2α did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2α that promotes resistance to RAF- and MEK-targeted therapies. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/27226552/Protein_Kinase_CK2α_Maintains_Extracellular_Signal_regulated_Kinase__ERK__Activity_in_a_CK2α_Kinase_independent_Manner_to_Promote_Resistance_to_Inhibitors_of_RAF_and_MEK_but_Not_ERK_in_BRAF_Mutant_Melanoma_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=27226552 DB - PRIME DP - Unbound Medicine ER -