Table 1.
CK2 regulated intracellular signaling pathways that are important for leukemogenesis and/or chemosensitivity in primary human AML cells [3,15,16,17,18,19,20,21,22,23,24,25,26,31,32,33]. The effects on five different pathways are summarized, and for each pathway we present CK2-targeted mediators (left column/target), the CK2 effect on the targeted pathway mediator (middle column), and the cellular consequences of CK2-mediated mediator phosphorylation (right column).
| Target | Phosphorylation | Cellular Consequences of Phosphorylation |
|---|---|---|
| Regulation of PI3K–Akt–mTOR signaling | ||
| Akt | Phosphorylation including Ser129 | Ser129 phosphorylation prevents dephosphorylation of Thr308; this leads leading to downstream mTOR signaling |
| Pten | Phosphorylation of Ser370, as well as several other residues | Inhibits its phosphatase activity, thereby preventing downregulation of PI3K-dependent signaling. Pten is destabilized both by this Ser370 phosphorylation and phosphorylation of Thr366 by glycogen synthase kinase 3 |
| Regulation of NFκB signaling | ||
| Ikk | Ser32 and Ser36 phosphorylation | Ikk activation with downstream phosphorylation of IκBα |
| IκBα | Increased C-terminal phosphorylation through a direct CK2 effect and indirectly via Ikk | Phosphrylation of this inhibitor promotes its degradation, leading to NFκBp65 translocation to the nucleus |
| NFκBp65 | Ser529 phosphorylation | Increased transcriptional activity |
| Jak2/Stat3 signaling | ||
| Jak1 | Activated by phosphorylation | Increased survival and proliferation, modulated cytokine release, and thereby altered communication with neighboring non-leukemic and AML-supporting cells |
| Jak2 | Activated by phosphorylation | |
| Stat3 | Activated by phosphorylation | |
| DNA damage responses | ||
| Xrcc4 | The general effect of CK2-mediated phosphorylation is an increased association with DNA–repair protein complexes | Double strand DNA repair |
| Mre11 | Involved in several mechanisms of DNA repair, incuding double-strand repair | |
| Xrcc1 | Single-strand DNA repair | |
| Mdc1 | A scaffold protein involved in the early steps of DNA repair | |
| Wnt/β-cathenin signaling | ||
| Dvl | Multisite modulation of the signaling pathway through phosphorylation of different mediators | Reducing β-cathenin degradation |
| β-cathenin | Increased nuclear translocation and transcriptional ctivity | |
| TCF/LEF | Increased transcription factor activity | |
Abbreviations: Dvl, dishevelled proteins; mTOR, molecular target of rapamycin; Pdk1, phosphoinositide-dependent kinase 1; Pten, phosphatase and tensin homolog.