Involvement of Protein Kinase CK2 in Angiogenesis and Retinal Neovascularization

Ljubimov, Alexander V.; Caballero, Sergio; Aoki, Annette M.; Pinna, Lorenzo A.; Grant, Maria B.; Castellon, Raquel

doi:10.1167/iovs.04-0686

Cited by 73 publications

(69 citation statements)

References 71 publications

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“…Two CK2 inhibitors, namely emodin and tetrabromobenzotriazole (TBB), were found to significantly reduce retinal neovascularization [66]. Later on, it was tested whether the effect of CK2 inhibitors would be enhanced if they were contributed with other anti-angiogenic drugs with a different mode of action.…”

Section: Ck2 and Angiogenesismentioning

confidence: 99%

Protein Kinase CK2 and Angiogenesis

Montenarh¹

2014

Adv Clin Exp Med

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CK2 is an ubiquitously expressed protein kinase, which is composed of two catalytic a-and a'-and two noncatalytic b-subunits. CK2 protein levels and kinase activity is elevated in rapidly proliferating cells including cancer cells. There is increasing evidence that CK2 also plays an essential role in angiogenesis, either by interaction or phosphorylation of growth factors or by phosphorylation or binding to proteins in signalling cascades, which are implicated in angiogenesis. Over the last ten years a great number of inhibitors for CK2 were detected, two of them are now in clinical phase II trials for the treatment of cancer patients. Some of these inhibitors were also found to be active in the inhibition of angiogenesis. Thus, CK2 inhibitors probably together with inhibitors of other signalling molecules involved in angiogenesis might be powerful tools for the treatment of cancer and cancer connected angiogenesis (Adv Clin Exp Med 2014, 23, 2, 153-158).

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Section: Ck2 and Angiogenesismentioning

confidence: 99%

Protein Kinase CK2 and Angiogenesis

Montenarh¹

2014

Adv Clin Exp Med

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“…Early reports describing the use of CK2 inhibitors in vivo in mouse models, in which no evident toxicity has been observed, supported this notion. 55,56 Most importantly, very recently a phase-I clinical trial started in USA, sponsored by Cylene Pharmaceuticals, which is testing safety, tolerability and highest dose level of the CK2 inhibitor CX-4945 in patients with advanced solid cancers, Castleman's disease or MM (NCT00891280). Preliminary results have displayed very encouraging results, 46 and later a myeloma-dedicated phase-I trial has started (NCT01199718).…”

Section: The Therapeutic Potential Of Ck2 Inhibition In Blood Tumorsmentioning

confidence: 99%

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis. Leukemia (2012Leukemia ( ) 26, 1174Leukemia ( --1179 doi:10.1038/leu.2011; published online 13 January 2012Keywords: hematopoiesis; blood tumors; protein kinase CK2; kinase inhibitors INTRODUCTION Protein kinase CK2 is a highly conserved pleiotropic acidophilic serine-threonine kinase whose essential role in several cellular processes has been increasingly appreciated over the last decade. 1 Structurally, CK2 is a tetrameric enzyme, composed by the assembly of two catalytic (a and/or a') and two regulatory b subunits. The catalytic and regulatory subunits may also be present in the cell as unassembled molecules and it seems that this state is associated with distinct and specific functions. The two catalytic subunits a and a' share 90% sequence homology in their N-terminal region. The regulatory subunit b instead does not have any similarity to the other two subunits. 2 CK2 recognizes motifs characterized by a S/T N-terminal to acidic amino acids, its minimum consensus being S/T-X-X-Ac, where X is any amino acid and Ac is a residue with a carboxylic or phosphorylated side chain (E, D, pS, pY).The spectrum of actions of this kinase is impressive as it can phosphorylate hundreds of substrate proteins, which are involved in disparate cellular processes, such as regulation of cell structure, division, proliferation, programmed death, DNA damage repair, protein translation, gene transcription, organelle function and so forth. 3 It has been estimated that a substantial proportion of the human phosphoproteome (up to 20%) is generated by CK2 alone. For this reason, CK2 has long been viewed as a 'non-targetable' kinase for therapeutic purposes.The essential role of CK2 for cell and organism life is underscored by th...

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“…CK2 is markedly augmented in a wide range of cancers (18) and appears to enhance malignant transformation by creating a more hospitable environment for tumor growth (19). CK2 also stimulates angiogenesis (20) as well as multidrug resistance (21). Pandolfi and coworkers demonstrated that the tumor suppressor promyelocytic leukemia protein (PML) is a physiologic substrate of CK2 (22).…”

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confidence: 99%

Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2

Chakraborty

Werner

Koldobskiy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PESTsequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.

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Involvement of Protein Kinase CK2 in Angiogenesis and Retinal Neovascularization

Abstract: This is the first demonstration of the involvement of ubiquitous protein kinase CK2 in angiogenesis. Naturally derived CK2 inhibitors may be useful for treatment of proliferative retinopathies.

Cited by 73 publications

References 71 publications

Protein Kinase CK2 and Angiogenesis

Protein Kinase CK2 and Angiogenesis

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2

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