Casein kinase 2beta as a novel enhancer of activin-like receptor-1 signaling.
ALK-1 is a transforming growth factor beta (TGF-beta) 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-beta superfamily coreceptor, endoglin, form a heteromeric complex and bind similar TGF-beta superfamily ligands, their signaling mechanisms remain poorly characterized. Here we report the identification of CK2beta, the regulatory subunit of protein kinase CK2, as a novel enhancer of ALK-1 signaling. The cytoplasmic domain of ALK-1 specifically binds to CK2beta in vitro and in vivo. NAAIRS mutagenesis studies define amino acid sequences 181-199 of CK2beta and 207-212 of ALK-1 as the interaction domains, respectively. The ALK-1/CK2beta interaction specifically enhanced Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation in response to TGF-beta1 and BMP-9 treatment. In a reciprocal manner, siRNA-mediated silencing of endogenous CK2beta inhibited TGF-beta1 and BMP-9-stimulated Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation. Functionally, CK2beta enhanced the ability of activated or ligand-stimulated ALK-1 to inhibit endothelial cell migration. Similarly, ALK-1 and CK2beta antagonized endothelial tubule formation in Matrigel. These studies support CK2beta as an important regulator of ALK-1 signaling and ALK-1-mediated functions in endothelial cells.
Lee
Nam Y
NY
Department of Medicine, Duke University, Durham, NC, USA.
Haney
John C
JC
Sogani
Julie
J
Blobe
Gerard C
GC
D030301:Activin Receptors, Type II / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D047390:Casein Kinase II / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D021122:Protein Subunits; D051785:Smad Proteins; D047390:Casein Kinase II; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II