title: A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway.
abstract: 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.
authors.affiliation: Departments of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Luqin
authors.initials: L
authors.lastname: Deng
authors.forename: David W
authors.initials: DW
authors.lastname: Litchfield
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Fang-Tsyr
authors.initials: FT
authors.lastname: Lin
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Li
authors.forename: Bingdong
authors.initials: B
authors.lastname: Sha
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D010762:Phosphorylase a / Q000502:physiology; D011087:Polycythemia Vera / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050791:STAT Transcription Factors; D010762:Phosphorylase a; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D047390:Casein Kinase II; D048031:JNK Mitogen-Activated Protein Kinases