Casein Kinase 2 Linked to Dysfunctional JAK-STAT Signaling in Cancer Cells

The receptor is activated by a signal from interferon, interleukin, growth factors, or other chemical messengers. This activates the kinase function of JAK, which autophosphorylates itself. The STAT protein then binds to the phosphorylated receptor. STAT is then phosphorylated and translocates into the cell nucleus, where it binds to DNA and promotes transcription of genes responsive to STAT. Disrupted or dysregulated JAK-STAT functionality (usually by inherited or acquired genetic defects) can result in immune deficiency syndromes and cancers.

CK2 is a serine/threonine-selective protein kinase that is a tetramer of two alpha subunits and two beta subunits. The alpha subunits have the catalytic kinase domain. CK2 has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes.

Results published in the July 7, 2011, issue of the journal Blood revealed that CK2 interacted with a mutated form of JAK called JAK2V617F. Inhibition of CK2 with small interfering RNA or pharmaceuticals, suppressed JAK2V617F autophosphorylation and downstream signaling in both HEL92.1.7 cells and primary cells from PV patients. Furthermore, CK2 inhibitors potently induced apoptosis of HEL cells and PV cells.

“In discovering that the CK2 protein activates the JAK-STAT pathway, we can now look for ways to shut down both, which is important in cancer treatment, because if you shut down only one of these, cells can still grow,” said senior author Dr. Etty Benveniste, professor of cell biology at the University of Alabama. “These findings will help enable the development of drugs to target blocking both the pathway and the protein, of which the ultimate goal is causing cell death in tumors. There should be a time-limited response from both of these that should be of benefit to the host, but something happens in cancer and autoimmune diseases and neither is turned off, helping diseased cells grow.”

“Through this study, we provided clear evidence that activation of the JAK-STAT signaling pathway is dependent on the presence and/or activity of CK2 in tumor cells,” said Dr. Benveniste. “There are a number of pharmaceutical companies that are generating inhibitors for both of these and some are in clinical trials now. Because of our observations, companies that produce these inhibitors can now test drugs that inhibit both on patients. Some of that is starting to happen now in people with myleoproliferative disorders, and future studies are planned on glioblastoma multiforme, the deadliest brain tumor, and breast cancer.”

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