GCKIII (Germinal Center Kinase III) Kinases STK24 and STK25 (Serine/Threonine Kinase 24 and 25) Inhibit Cavernoma Development.

Abstract

Cavernous cerebral malformations can arise because of mutations in the <i>CCM1</i>, <i>CCM2</i>, or <i>CCM3</i> genes, and lack of <i>Cdc42</i> has also been reported to induce these malformations in mice. However, the role of the CCM3 (cerebral cavernous malformation 3)-associated kinases in cavernoma development is not known, and we, therefore, have investigated their role in the process. We used a combination of an in vivo approach, using mice genetically modified to be deficient in the CCM3-associated kinases STK24 and STK25 (serine/threonine kinases 24 and 25), and the in vitro model of human endothelial cells in which expression of <i>STK24</i> and <i>STK25</i> was inhibited by RNA interference. Mice deficient for both <i>Stk24</i> and <i>Stk25</i>, but not for either of them individually, developed aggressive vascular lesions with the characteristics of cavernomas at an early age. <i>Stk25</i> deficiency also gave rise to vascular anomalies in the context of <i>Stk24</i> heterozygosity. Human endothelial cells deficient for both kinases phenocopied several of the consequences of <i>CCM3</i> loss, and single <i>STK25</i> deficiency also induced <i>KLF2</i> expression, Golgi dispersion, altered distribution of β-catenin, and appearance of stress fibers. The CCM3-associated kinases STK24 and STK25 play a major role in the inhibition of cavernoma development.