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.

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