Toward the rational design of protein kinase casein kinase-2 inhibitors

Sarno, Stefania; Moro, Stefano; Meggio, Flavio; Zagotto, Giuseppe; Ben, Diego Dal; Ghisellini, Paola; Battistutta, Roberto; Zanotti, Giuseppe; Pinna, Lorenzo A.

doi:10.1016/s0163-7258(02)00185-7

Cited by 146 publications

(112 citation statements)

References 37 publications

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“…The cells also clearly expressed detectable levels of endogenous CKIIa (Figure 4a, lower panel). We treated both induced and noninduced cells with 60 mM 4,5,6,7-tetrabromo-2-benzotriazole (TBB), the most specific inhibitor of CKIIa activity available to date (Sarno et al, 2002). TBB was initially only tested in vitro and in plant cells (Battistutta et al, 2001;Sarno et al, 2001); however, a more recent study found 25-100 mM TBB to be effective in inhibiting the growth of T-cell lymphoma Jurkat cells (Ruzzene et al, 2002).…”

Section: Ckiia Forms a Complex With P210 And P190 Bcr/ablmentioning

confidence: 99%

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

et al. 2003

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Section: Ckiia Forms a Complex With P210 And P190 Bcr/ablmentioning

confidence: 99%

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

et al. 2003

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“…In this report, for the first time, we provide evidence that CK2 is involved in STAT1 phosphorylation. Using a specific inhibitor of CK2, TBB, which selectively inhibits this enzyme among a panel of 33 other kinases (Sarno et al, 2001(Sarno et al, , 2002, we inhibited serine phosphorylation of STAT1 in WT cells concomitantly with anchorage-independent growth (Figures 6b and 7a). We propose that STAT1 in WT functions as part of a CK2 signaling pathway behaving as a prosurvival factor possibly through interactions with other targets of CK2.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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“…Among the kinases, protein kinase 2 or CK2 is a constitutively active Ser/Thr protein kinase essential for cell viability (18). CK2 can target at least 200 proteins (19) and is implicated in a wide variety of cellular functions such as tRNA and rRNA synthesis, apoptosis.…”

mentioning

confidence: 99%

Phosphorylation by Protein Kinase CK2 Modulates the Activity of the ATP Binding Cassette A1 Transporter

Roosbeek

Peelman

Verhee

et al. 2004

Journal of Biological Chemistry

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In a previous characterization of the ABCA subfamily of the ATP-binding cassette (ABC) transporters, we identified potential protein kinase 2 (CK2) phosphorylation sites, which are conserved in eukaryotic and prokaryotic members of the ABCA transporters (Peelman, F., Labeur, C., Vanloo, B., Roosbeek, S., Devaud, C., Duverger, N., Denefle, P., Rosier, M., Vandekerckhove, J., and Rosseneu, M. (2003) J. Mol. Biol. 325, 259 -274). These phosphorylation residues are located in the conserved cytoplamic R1 and R2 domains, downstream of the nucleotide binding domains NBD1 and NBD2. To study the possible regulation of the ABCA1 transporter by CK2, we expressed the recombinant cytoplasmic domains of ABCA1, NBD1؉R1 and NBD2؉R2. We demonstrated that in vitro ABCA1 NBD1؉R1, and not NBD2؉R2, is phosphorylated by CK2, and we identified Thr-1242, Thr-1243, and Ser-1255 as the phosphorylated residues in the R1 domain by mass spectrometry. We further investigated the functional significance of the threonine and serine phosphorylation sites in NBD1 by site-directed mutagenesis of the entire ABCA1 followed by transfection into Hek-293 Tet-Off cells. The ABCA1 flippase activity, apolipoprotein AI and AII binding, and cellular phospholipid and cholesterol efflux were enhanced by mutations preventing CK2 phosphorylation of the threonine and serine residues. This was confirmed by the effect of specific protein kinase CK2 inhibitors upon the activity of wild type and mutant ABCA1 in transfected Hek-293 Tet-Off cells. The activities of the mutants mimicking threonine phosphorylation were close to that of wild type ABCA1. Our data, therefore, suggest that besides protein kinase A and C, protein kinase CK2 might play an important role in vivo in regulating the function and transport activity of ABCA1 and possibly of other members of the ABCA subfamily.The role of the ABCA1 1 transporter, a member of the subfamily A of the ATP binding cassette transporters, in the efflux of cellular phospholipids and cholesterol has become well established (2). Several studies link ABCA1 mutations to impaired cellular cholesterol and phospholipid efflux characteristic of Tangier disease and high density lipoprotein-deficiency patients (3-5). Expression of WT and mutant ABCA1 in cultured cells demonstrated the correlation between the level of expression and activity of the ABCA1 transporter, the extent of binding to the apolipoprotein AI (apoAI) acceptor and the efflux of cellular lipid (6).Human ABC transporters consist of a cytoplasmic nucleotide binding domain (NBD), which binds and hydrolyzes ATP, and of a membrane-spanning domain through which the substrate is translocated (7-8). Besides these elements, regulatory domains with putative phosphorylation sites were described in several human transporters (7). We carried out an extensive analysis of the subfamily A of the ABC transporters and showed that this subfamily consists of 13 human ABCA and of many eukaryotic and prokaryotic ABCA homologues (1). Multiple alignments of the subfamily A transporters de...

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Toward the rational design of protein kinase casein kinase-2 inhibitors

Cited by 146 publications

References 37 publications

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Phosphorylation by Protein Kinase CK2 Modulates the Activity of the ATP Binding Cassette A1 Transporter

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