CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations.

Abstract	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.
Authors	Xiangjian Zheng, Chong Xu, Annarita Di Lorenzo, Benjamin Kleaveland, Zhiying Zou, Christoph Seiler, Mei Chen, Lan Cheng, Jiping Xiao, Jie He, Michael A Pack, William C Sessa, Mark L Kahn
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 8 Pg. 2795-804 (Aug 2010) ISSN: 1558-8238 [Electronic] United States
PMID	20592472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Apoptosis Regulatory Proteins Intracellular Signaling Peptides and Proteins Membrane Proteins Microfilament Proteins Microtubule-Associated Proteins Muscle Proteins PDCD10 protein, human Proto-Oncogene Proteins Zebrafish Proteins krit1 protein, zebrafish pdcd10a protein, zebrafish moesin Protein Serine-Threonine Kinases STK25 protein, human
Topics	Amino Acid Sequence Animals Apoptosis Regulatory Proteins (chemistry, genetics, physiology) Cardiovascular System (embryology) Conserved Sequence Hemangioma, Cavernous, Central Nervous System (etiology) Humans Intracellular Signaling Peptides and Proteins (physiology) Membrane Proteins (chemistry, genetics, physiology) Microfilament Proteins (metabolism) Microtubule-Associated Proteins (physiology) Molecular Sequence Data Muscle Proteins Phosphorylation Protein Serine-Threonine Kinases (physiology) Proto-Oncogene Proteins (chemistry, genetics, physiology) Sequence Alignment Signal Transduction (physiology) Zebrafish Zebrafish Proteins (chemistry, genetics, physiology)

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