Abstract
Kallistatin is a unique serine proteinase inhibitor and heparin-binding protein. A previous study conducted by our group indicated that kallistatin has antiangiogenic and antitumoral activities. In the present study, we report that kallistatin specifically binds to membrane surface-expressed nucleolin with high affinity. Antibody-mediated neutralization or siRNA-induced nucleolin knockdown results in loss of kallistatin suppression of endothelial cell proliferation and migration in vitro and tumor angiogenesis and growth in vivo. In addition, we show that kallistatin is internalized and transported into cell nuclei of endothelial cells via nucleolin. Within the nucleus, kallistatin inhibits the phosphorylation of nucleolin, which is a critical step required for cell proliferation. Thus, we demonstrate that nucleolin is a novel functional receptor of kallistatin that mediates its antiangiogenic and antitumor activities. These findings provide mechanistic insights into the inhibitory effects of kallistatin on endothelial cell growth, tumor cell proliferation, and tumor-related angiogenesis.
Highlights
Angiogenesis denotes the proliferation of endothelial cells and outgrowth of new capillaries from preexisting vessels
Soluble heparin was used for coimmunoprecipitation experiments to assess whether kallistatin interacts with nucleolin via its heparinbinding sites
The results indicated that increasing concentrations of soluble heparin induced gradual disassociation of the nucleolin and kallistatin complex
Summary
Angiogenesis denotes the proliferation of endothelial cells and outgrowth of new capillaries from preexisting vessels. This process is critical for tumor growth and facilitates tumor invasion and metastasis. The heparin-binding domain is essential in suppressing VEGF-mediated endothelial cell proliferation and migration [13]. In many ligand-receptor systems initial ligand binding occurs onto abundantly expressed lowaffinity receptors; these in turn recruit the ligand to the cell surface, where it activates high-affinity receptors that transduce the corresponding signals. Kallistatin acts by competing with VEGF and bFGF for binding to HSPGs. Kallistatin acts by competing with VEGF and bFGF for binding to HSPGs This occurs at a low affinitybinding site, and suppresses pro-angiogenic signaling by these two growth factors [6]
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