Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling

ALK‐1 is a transforming growth factor β(TGF‐β) superfamily receptor that is predominantly expressed in endothelial cells and is essential for angiogenesis, as demonstrated by the embryonic lethal phentoype when targeted for deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia. Although ALK‐1 and the endothelial‐ specific TGF‐P superfamily coreceptor, endoglin, form a heteromeric complex and bind similar TGF‐β super‐ family ligands, their signaling mechanisms remain poorly characterized. Here we report the identification of CK2β, the regulatory subunit of protein kinase CK2, as a novel enhancer of ALK‐1 signaling. The cytoplas‐ mic domain of ALK‐1 specifically binds to CK2β in vitro and in vivo. NAAIRS mutagenesis studies define amino acid sequences 181‐199 of CK2β and 207‐212 of ALK‐1 as the interaction domains, respectively. The ALK‐1/ CK2β interaction specifically enhanced Smad1/5/8 phosphorylation and ALK‐1‐mediated reporter activa‐ tion in response to TGF‐β 1 and BMP‐9 treatment. In a reciprocal manner, siRNA‐mediated silencing of endog‐ enous CK2β inhibited TGF‐β 1 and BMP‐9‐stimulated Smad1/5/8 phosphorylation and ALK‐1‐mediated re‐ porter activation. Functionally, CK2β enhanced the ability of activated or ligand‐stimulated ALK‐1 to inhibit endothelial cell migration. Similarly, ALK‐1 and CK2βantagonized endothelial tubule formation in Matrigel. These studies support CK2β as an important regulator of ALK‐1 signaling and ALK‐1‐mediated functions in endothelial cells.—Lee, N. Y., Haney, J. C., Sogani, J., Blobe, G. C. Casein kinase 2β as a novel enhancer of activin‐like receptor‐1 signaling. FASEB J. 23, 3712‐3721 (2009). www.fasebj.org