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

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 inflammati...

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Autores principales: Aparicio-Siegmund, Samadhi, Sommer, Jan, Monhasery, Niloufar, Schwanbeck, Ralf, Keil, Eric, Finkenstädt, David, Pfeffer, Klaus, Rose-John, Stefan, Scheller, Jürgen, Garbers, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039151/
https://www.ncbi.nlm.nih.gov/pubmed/24742922
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author Aparicio-Siegmund, Samadhi
Sommer, Jan
Monhasery, Niloufar
Schwanbeck, Ralf
Keil, Eric
Finkenstädt, David
Pfeffer, Klaus
Rose-John, Stefan
Scheller, Jürgen
Garbers, Christoph
author_facet Aparicio-Siegmund, Samadhi
Sommer, Jan
Monhasery, Niloufar
Schwanbeck, Ralf
Keil, Eric
Finkenstädt, David
Pfeffer, Klaus
Rose-John, Stefan
Scheller, Jürgen
Garbers, Christoph
author_sort Aparicio-Siegmund, Samadhi
collection PubMed
description 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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spelling pubmed-40391512014-06-10 Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation Aparicio-Siegmund, Samadhi Sommer, Jan Monhasery, Niloufar Schwanbeck, Ralf Keil, Eric Finkenstädt, David Pfeffer, Klaus Rose-John, Stefan Scheller, Jürgen Garbers, Christoph Oncotarget Research Paper 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. Impact Journals LLC 2014-03-23 /pmc/articles/PMC4039151/ /pubmed/24742922 Text en Copyright: © 2014 Aparicio-Siegmund et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Aparicio-Siegmund, Samadhi
Sommer, Jan
Monhasery, Niloufar
Schwanbeck, Ralf
Keil, Eric
Finkenstädt, David
Pfeffer, Klaus
Rose-John, Stefan
Scheller, Jürgen
Garbers, Christoph
Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title_full Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title_fullStr Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title_full_unstemmed Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title_short Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation
title_sort inhibition of protein kinase ii (ck2) prevents induced signal transducer and activator of transcription (stat) 1/3 and constitutive stat3 activation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039151/
https://www.ncbi.nlm.nih.gov/pubmed/24742922
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