Fig. 2

CK2 roles in cancer. Signaling pathways by which CK2 exerts its specific functions in cancer cells are depicted. For each pathway, CK2 targets are shown only in case their effects in tumorigenesis have been dissected (not showing CK2 substrates whose phosphorylation does not produce a well-defined effect). Double arrows indicate a dynamic equilibrium that moves toward the longest arrow direction; inhibitions are indicated by bar-headed arrows. a Major mechanisms by which CK2 prevents caspase activation. CK2 phosphorylation of BID prevents its cleavage to the truncated form (tBID) and its consequent migration to the mitochondria; this event blocks the apoptotic cascade dependent on the cytosolic release of proapoptotic factors cytochrome c (Cyt c), an activator of caspase 9 via APAF-1 (apoptotic protease activating factor-1), and Smac/DIABLO, a repressor of IAP (inhibitor of apoptosis) proteins. Furthermore, CK2 directly phosphorylates and prevents the activation of caspase-3, and promotes the action of the caspase inhibitor ARC, which blocks caspase 8. b CK2 effects on multidrug resistance (MDR). CK2 reduces the cancer cell response to chemotherapeutic drugs by promoting the expression of the three major drug extrusion pumps, namely MRP1, P-gp, and BCRP. MRP1 and P-gp are also directly activated by CK2. c Major actions of CK2 on the unfolded protein response pathway. CK2 acts on different branches of the unfolded protein response, with the effect of preventing the final apoptotic outcome (by blocking the PERK signaling) and driving towards the survival response (by supporting the IRE1 signaling). d CK2 regulation of chaperone proteins. CK2 directly controls the activity of HSP70 and CDC37 (HSP90 co-chaperone), and protects HSP27 from degradation. These chaperones, in turn, stabilize and maintain the activity of oncogenic proteins, especially protein kinases (oncokinases). e Major mechanisms of CK2 control on tumor suppressor proteins. CK2 promotes p53 degradation through the phosphorylation of the ubiquitin-specific peptidase 7 (USP7S); this in turn stabilizes MDM2 with the final effect of targeting p53 to the proteasome. IKAROS is directly phosphorylated by CK2, reducing its DNA-binding affinity and promoting its degradation. CK2 also directly phosphorylates PML; this drives its proteasome-mediated degradation, and finally reduces its function of promoting senescence and apoptosis