title: Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation.
abstract: The Janus kinase / signal transducer and activator of transcription (Jak/STAT) pathway can be activated by many different cytokines, among them all members of the Interleukin (IL-)6 family. Dysregulation of this pathway, resulting in its constitutive activation, is associated with chronic inflammation and cancer development. In the present study, we show that activity of protein kinase II (CK2), a ubiquitously expressed serine/threonine kinase, is needed for induced activation of STAT1 and STAT3 by IL-6 classic and trans-signaling, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1). Inhibition of CK2 efficiently prevented STAT phosphorylation and inhibited cytokine-dependent cell proliferation in a Jak1-dependent manner. Conversely, forced activation of CK2 alone was not sufficient to induce activation of the Jak/STAT signaling pathway. Inhibition of CK2 in turn inhibited Jak1-dependent STAT activation by oncogenic gp130 mutations. Furthermore, CK2 inhibition diminished the Jak1- and Src kinase-dependent phosphorylation of a constitutively active STAT3 mutant recently described in human large granular lymphocytic leukemia. In conclusion, we characterize CK2 as an essential component of the Jak/STAT pathway. Pharmacologic inhibition of this kinase is therefore a promising strategy to treat human inflammatory diseases and malignancies associated with constitutive activation of the Jak/STAT pathway.
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;
authors.forename: Samadhi
authors.initials: S
authors.lastname: Aparicio-Siegmund
authors.forename: Jan
authors.initials: J
authors.lastname: Sommer
authors.forename: Niloufar
authors.initials: N
authors.lastname: Monhasery
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwanbeck
authors.forename: Eric
authors.initials: E
authors.lastname: Keil
authors.forename: David
authors.initials: D
authors.lastname: Finkenstädt
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053612:Janus Kinases; D047390:Casein Kinase II
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