期刊
BLOOD
卷 118, 期 1, 页码 156-166出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-01-266320
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资金
- National Center for Research Resources [S10 RR-27822]
- UAB Lung Health Center
- National Institutes of Health [NS-54158, NS-45290, NS-36765, NS-66332, GM-65959, DK-46395]
- Army Research Office [51894LS]
- Canadian Cancer Society Research Institute
- MPD Foundation, Chicago, IL
- [U54 CA100949]
- [P30 AT050948]
- [P30 DK079337]
JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs. (Blood. 2011;118(1):156-166)
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