Cerebral cavernous malformation is a common human vascular disease that arises 
due to loss-of-function mutations in genes encoding three intracellular adaptor 
proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3. 
CCM1, CCM2, and CCM3 interact biochemically in a pathway required in endothelial 
cells during cardiovascular development in mice and zebrafish. The downstream 
effectors by which this signaling pathway regulates endothelial function have 
not yet been identified. Here we have shown in zebrafish that expression of 
mutant ccm3 proteins (ccm3Delta) known to cause cerebral cavernous malformation 
in humans confers cardiovascular phenotypes identical to those associated with 
loss of ccm1 and ccm2. CCM3Delta proteins interacted with CCM1 and CCM2, but not 
with other proteins known to bind wild-type CCM3, serine/threonine protein 
kinase MST4 (MST4), sterile 20-like serine/threonine kinase 24 (STK24), and 
STK25, all of which have poorly defined biological functions. Cardiovascular 
phenotypes characteristic of CCM deficiency arose due to stk deficiency and 
combined low-level deficiency of stks and ccm3 in zebrafish embryos. In cultured 
human endothelial cells, CCM3 and STK25 regulated barrier function in a manner 
similar to CCM2, and STKs negatively regulated Rho by directly activating 
moesin. These studies identify STKs as essential downstream effectors of CCM 
signaling in development and disease that may regulate both endothelial and 
epithelial cell junctions.