Oncotarget

Research Papers:

Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation

Samadhi Aparicio-Siegmund, Jan Sommer, Niloufar Monhasery, Ralf Schwanbeck, Eric Keil, David Finkenstädt, Klaus Pfeffer, Stefan Rose-John, Jürgen Scheller and Christoph Garbers _

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Oncotarget. 2014; 5:2131-2148. https://doi.org/10.18632/oncotarget.1852

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Abstract

Samadhi Aparicio-Siegmund1, Jan Sommer1, Niloufar Monhasery1, Ralf Schwanbeck2, Eric Keil3, David Finkenstädt3, Klaus Pfeffer3, Stefan Rose-John2, Jürgen Scheller1 and Christoph Garbers1,4

1 Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany;

2 Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany;

3 Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine University, Düsseldorf, Germany

4 Present address: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany

Correspondence:

Jürgen Scheller, email:

Christoph Garbers, email:

Keywords: STAT3, cytokines, tumor, oncogene, signal transduction

Received: February 11, 2014 Accepted: March 22, 2014 Published: March 23, 2014

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.


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