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Updated: Aug 11, 2026
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization
Alexander V Ljubimov1, Sergio Caballero, Annette M Aoki
1Ophthalmology Research Laboratories, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-2025, Los Angeles, CA 90048, USA. ljubimov@cshs.org
Purpose:
The purpose of the study was to characterize signaling intermediates involved in angiogenic responses of retinal endothelial cells (RECs) to the extracellular matrix and growth factors, by using specific inhibitors.
Methods:
Tubelike structure formation and the development of secondary sprouts on a basement membrane (BM) matrix, cell proliferation, and cell migration were studied in cultures of bovine and human RECs. Specific inhibitors were tested for inhibition of retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
Results:
In initial experiments, the broad-spectrum protein kinase inhibitors, H7 and H89, stabilized REC tubes on BM matrix and inhibited secondary sprouting, cell migration, and cell proliferation. Among more specific kinase inhibitors tested, only inhibitors of protein kinase CK2 (formerly, casein kinase II), such as emodin and DRB, were able to duplicate the effects of H7 and H89. Actinomycin D caused only minor changes in angiogenic assays, suggesting that CK2's effects on REC did not involve its known impact on transcription. The extent of retinal neovascularization in a mouse OIR model was reduced >70% (versus untreated or vehicle-treated groups) after treatment with emodin (6 days at 60 mg/kg per day) and by approximately 60% after treatment at the same dose with TBB, the most specific CK2 inhibitor known. In the treated retinas, the main vascular tree had minimal changes, but the neovascular tufts were greatly reduced in number or absent.
Conclusions:
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.
Insights
Protein kinase CK2 (casein kinase II) is crucial for retinal endothelial cell (REC) proliferation and migration, key processes in angiogenesis. CK2 inhibitors significantly reduced retinal neovascularization in a mouse model, suggesting therapeutic potential for proliferative retinopathies.
Area of Science:
- Cell Biology
- Molecular Biology
- Ophthalmology
Background:
- Angiogenesis, the formation of new blood vessels, is a complex process involving retinal endothelial cells (RECs).
- Understanding the signaling pathways that regulate REC responses to the extracellular matrix and growth factors is critical for treating angiogenic disorders.
- Proliferative retinopathies are characterized by aberrant retinal neovascularization.
Purpose of the Study:
- To investigate the role of specific signaling intermediates in the angiogenic responses of RECs.
- To characterize the involvement of protein kinase CK2 in REC behavior and retinal neovascularization.
Main Methods:
- Studied tubelike structure formation, secondary sprouting, cell proliferation, and migration in bovine and human RECs cultured on basement membrane matrix.
- Utilized specific protein kinase inhibitors, including broad-spectrum inhibitors (H7, H89) and specific CK2 inhibitors (emodin, DRB, TBB).
- Assessed the efficacy of inhibitors in reducing retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
Main Results:
- Broad-spectrum inhibitors H7 and H89 stabilized REC tubes and inhibited sprouting, migration, and proliferation.
- Specific inhibitors of protein kinase CK2 (emodin, DRB) replicated the effects of H7 and H89.
- CK2 inhibition did not appear to involve transcriptional regulation, as indicated by minimal effects of Actinomycin D.
- Emodin and TBB significantly reduced retinal neovascularization in the OIR mouse model (>70% and ~60% reduction, respectively), with minimal impact on the main vascular tree but a marked reduction in neovascular tufts.
Conclusions:
- This study provides the first evidence for the involvement of the ubiquitous protein kinase CK2 in angiogenesis.
- Naturally derived CK2 inhibitors show promise as a potential therapeutic strategy for treating proliferative retinopathies.
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