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.

The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

“…Janus kinases are constitutively associated with gp130, and their activation leads to the tyrosine phosphorylation of specific motifs within the intracellular domain of gp130. IL-6 activates gene transcription mainly via the STAT1 and STAT3 proteins [10]. The research conducted to date confirms the vital role of the JAK/STAT pathway in RA pathogenesis [9].…”

The biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity

“…Apart from STAT activation IL-27 also leads to the activation of ERK, p38 MAPK and Akt signaling, which could be shown in intestinal epithelial and liver cell lines [19,23]. In DLD-1 cells inhibition of p38 MAPK lead to reduced IL-27-induced proliferation.…”

“…Concerning the signaling of IL-6-type cytokines only Jak1 has non-redundant functions and loss of Jak1 cannot be compensated by the other two kinases [19,20]. WSX-1 appears to have the same box 1 motif that mediates the interaction with the Jak kinases in the cytoplasmic portion of the receptor.…”

The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

“…Other small molecules that interfere with the Jak/STAT signaling cascade, for example inhibitors of protein kinase II [50], are just entering clinical trials.…”