Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia

Abstract

Signaling networks that regulate cellular proliferation often involve complex interactions between several signaling pathways. In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. Both CK2 and GSK-3 are potential targets for anti-leukemia treatment. Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN. More recent data demonstrate another mechanism through which CK2 promotes the PI3K pathway – via transcriptional regulation of PI3K pathway genes by the newly-discovered CK2-Ikaros axis. Together, these data suggest that the CK2 and GSK-3 pathways regulate AKT/PI3K signaling in leukemia via two complementary mechanisms: a) direct phosphorylation of PTEN and b) transcriptional regulation of PI3K-promoting genes. Functional interactions between CK2, Ikaros and GSK3 define a novel signaling network that regulates proliferation of leukemia cells. This regulatory network involves both direct posttranslational modifications (by CK and GSK-3) and transcriptional regulation (via CK2-mediated phosphorylation of Ikaros). This information provides a basis for the development of targeted therapy for leukemia.

Faculty Opinions recommendation of Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2.

“…Casein kinases have previously been shown to regulate PI3K signaling by phosphorylation of PTEN (37). This activation of PI3K signaling by CSNK2A1 is synergistic with GSK-3, which does not phosphorylate BCAP in our in vitro kinase assay (38). Casein kinases have also been linked to innate immunity, by phosphorylation of various proteins in the NF-B pathway (30,39,40).…”

Phosphorylation of the multifunctional signal transducer B-cell adaptor protein (BCAP) promotes recruitment of multiple SH2/SH3 proteins including GRB2

“…Casein kinases have previously been shown to regulate PI3K signaling by phosphorylation of PTEN (37). This activation of PI3K signaling by CSNK2A1 is synergistic with GSK-3, which does not phosphorylate BCAP in our in vitro kinase assay (38). Casein kinases have also been linked to innate immunity, by phosphorylation of various proteins in the NF-κB pathway (30, 39, 40).…”

IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update

“…Another potential target is the serine/threonine protein kinase CK2, which is a posttranslational activator of constitutive PI3K/Akt signaling in T-ALL cells by inhibiting PTEN (Silva et al, 2008). CK2 was shown to play a key role in promoting the proliferation of ALL cells of both B and T cell origin (Gomes et al, 2014; Gowda et al, 2017a, 2017b; Silva et al, 2008) and was recently shown to be required for optimal IL-7-mediated signaling, and consequent IL-7-dependent T-ALL cell cycle progression and viability (Melao et al, 2016). CK2 was also required for the viability of mutant IL-7R-expressing leukemia T-cells.…”